This document presents a case of pediatric head injury. It discusses a case of an 11-year-old boy who was unrestrained in a motor vehicle collision and was ejected. He presented with a Glasgow Coma Scale of 4 and required intubation. Imaging showed open skull fractures, brain swelling, and hemorrhages. The document then reviews the epidemiology, pathophysiology, clinical features, decision rules, and management of minor, moderate and severe pediatric head injuries. Special considerations for pediatric head injuries include the increased risk of abuse in young children and anatomical differences that make the skull more vulnerable to injury compared to adults.

1. Daniel Kwan, MD

2. Objectives
 Present a case of pediatric head injury.
 Examine the uniqueness of pediatric head injuries.
 Discuss the clinical presentations and decision rules
for minor head injury
 Review the pathophysiology and treatment of
moderate/severe head injury.
 Review abusive head injury and other pertinent
pediatric head injury types.

3. Case
 CC: Stat Trauma
 HPI: 11 yo boy with no PMH who presents after MVC
rollover. Pt was unrestrained passenger and was
ejected. EMS found pt to be GCS 4. Pt intubated at
outside hospital. Pt decompensated prior going to the
CT scanner. Pt also had emergent left chest
thoracostomy placed. Transferred to CRMC.

4. Case
 PMH: none
 PSH: none
 Med: None
 Family hx: non-contributory
 Social history: lives with mother and father

5. Physical Exam
 VS: 98/52, 99, 12, 35.5, 100% (ETT)
 Neuro: GCS 4T (decerebrate posturing)
 Head: Open comminuted bifrontal skull fractures.
Multiple contusions. 4 cm frontal laceration.
 Pupils: Fixed and non-reactive (4 mm bilaterally)
 Neck: Contusions/ecchymosis to right anterior neck.
Carotid pulses 2+
 Chest: chest contusions. L chest tube
 Heart: RRR, no m/g/r

6. Physical Exam
 Abd: soft, distended
 Pelvis: stable, atraumatic
 GU: Normal genitalia
 Rectal: normal tone
 Extrem
 BUE: Contusions, swelling. Decerebrate posturing
 RLE: Contusions, abrasions
 LLE: Midshaft left femur deformity
 Back: No signs of blunt or penetrating trauma.

7. Labs
 ABG: 7.30/339/39/19
 Chem 10:
 Na: 129, K: 3.7, Bicarb- 22, BUN: 12, Cr 0.7, Glc 206
 CBC: 14.7/6.6/252
 PT/INR: 19.4/1.7
 UA- normal

8. CXR
 Small PTX
 Possible pulm
contusion

9. CT Chest/Abd/Pelvis
 L residual PTX
 Chest tube in place
 Pulmonary
Contusion

10. Head CT
 Multiple
Comminuted
skull fx
 Underlying L
EDH with
midline shift of 7
mm
 IPH and DAI

11. Other Imaging
 Pelvis XR- no fracture
 L femur XR- midshaft femur fracture
 CT C spine- no fracture
 FAST- possible minimal fluid on bladder view

12. Epidemiology
 650,000 to 1 million children evaluated for head trauma per year
 80-90% are mild
 In developed countries, TBI is the most common cause of death and
disability in childhood.
 Causes
 Infants: Abuse
 Toddlers: Abuse and falls
 School-aged: Injuries (play and sports) and MVCs
 Adolescents
 MVCs and assault
 ETOH can complicate assessments of injuries.
 Across all age groups, males > females in minor head injuries.

13. Pathophysiology
 Acceleration
 Moving object hits stationary head
 Least harmful
 Deceleration
 Moving head strikes stationary object.
 Most severe brainstem injuries
 Rotational
 Vigorous shaking
 Head hit at an angle
 Widespread injury including large SDH
 Direct blow
 Direct blow fracture
 EDH from either middle meningeal artery or dural venous sinuses

14. Pediatric Uniqueness
 Younger children have more distensible skulls
 Less protection in infants/toddlers
 Infant cranial sutures are open
 Toddler cranial cortex is thin.
 Very young children have higher mortality than older
children with the same injury.
 Limited history and exam at young age
 Underestimation of injuries
 Reluctance to start invasive procedures

15. Pediatric Uniqueness
 Increased probability of injury in infants/toddlers
 Large calvaria and weak cervical muscles
 Coordination and balance is poor
 Dependent on caregivers
 For supervision and safety equipment
 Non-accidental trauma.
 Stronger frontal bone
 Frontal sinus develops after 8-10 years old.
 Types of TBI
 Less traumatic mass lesions (except SDH)
 Less hemorrhagic contusion
 More diffuse brain swelling and axonal injury

16. Degrees of Head Injury
 Minor: GCS 13-15
 Moderate: GCS 9-13
 Severe: GCS <= 8

17. Pediatric GCS

19. Minor Head Injury
 85% of pediatric head injuries are classified as mild.
 About 400,000 ED visits per year particularly children
ages 0 to 4.

20. Clinical Features
 History
 Mechanism from caregivers, witnesses, EMS
 History incompatible with children’s age or situation.
 Clinical decision rules- PECARN
 Temporal changes or persistence of symptoms.
 Worsening sx- intracranial injury
 Persistence of HA, confusion, amnesia  concussion
 Ask child directly if verbal. Ask caregiver if preverbal

21. Clinical Features
 High risk
 Suspicion of child abuse
 Altered mental status
 Persistent vomiting
 Seizure following injury
 Loss of consciousness (> 5 seconds)
 Anticoagulated
 Shunt
 Intermediate risk
 Vomiting that is self-limited
 LOC that is brief (< 5 seconds)
 Resolved lethargy or irritability
 Behavior change by caregiver
 High risk mechanism (fall > 3 feet, ejection, etc.)
 Unwitnessed trauma of concern (e.g.: fall in another room with possible LOC)
 Age < 3 months with nontrivial trauma

22. Physical Exam
 ABCDE
 Proper fitting C-Collar
 Head to toe assessment for trauma.
 Neuro
 MSK
 Fundoscopic: particularly retinal hemorrhages
 High risk
 Suspicion of child abuse
 Focal neurologic findings
 Acute skull fracture, including depressed or basilar skull fracture
 Bulging fontanelle
 Intermediate risk
 Scalp hematoma (particularly nonfrontal and < 2 years old)
 Skull fracture > 24 hours old (non-acute)

23. Basilar Skull Fracture Signs
 Raccoon Eyes
 Battle’s Sign
 Hemotympanum
 CSF/Blood Rhinorrhea

24. To CT or Not to CT
 Benefits of CT
 Early identification can reduce morbidity/mortality.
 Children have atypical or vague symptoms
(vomiting, behavior change).
 Reassure parents.
 Disadvantages
 Head CT can be expensive (Avg charge ~$996)
 Radiation exposure
 1 head CT 1/1500 lifetime risk of death 2/2 cancer in 1 year old
 1/5000 lifetime risk in 10 year old
 Test threshold- no imaging was when probability of ciTBI
was less than 0.9%.1
1. Hennelly, KE., et al. Pediatric Traumatic Brain Injury and Radiation Risks: A Clinical
Decision Analysis. The Journal of Pediatrics. 2012;162:392-397.

25. Expert Panel Recommendations
 In 1999, a study of 608 infants and children < 2 years of
age. 2
 5% incidence of ICH
 Higher incidence in infants < 2 months old
 ½ of pts with ICH had clinical symptoms or signs
suggestive of brain injury.
 Virtually all had scalp hematoma.
 Follow-up study
 Skull fx and ICH correlated with hematoma size (med to
large), character (boggy), and location (non-frontal)
2. Schutzman SA, et al. Evaluation and management of children younger than two years old with apparently
minor head trauma: Proposed guidelines. Pediatrics 107: 983, 2001

26. Expert Panel Recommendations
High Risk Intermediate
Risk for ICH
Intermediate
Risk for Skull
Fracture
Low Risk
Depressed Mental
status
Vomiting 3-4 times Significant
mechanism
Low risk mech
Focal Neuro Finding LOC < 1 min Large nonfrontal
scalp hematoma
Asymptomatic,
normal exam
Acute (<24h) Skull
Fx
Resolved lethargy or
irritability
Fall onto hard
surface
>2h since injury
Basilar or depressed
skull fx
Caretaker concern Vague hx but signs or
sx of head trauma
Older age (>12 Mo)
Irritability Skull fx > 24h old
Vomiting > 5x in 6h
Seizure
LOC > 1 min
Bulging Fontanelle
Recommendation Recommendation Recommendation Recommendation
CT Scan Obs 4-6 h or CT scan Obs 4-6h or CT or
XR
No imaging

27. Decision Rules
 Assisting clinical decision making about
neuroimaging in children with minor head trauma.
 3 of the largest derived rules
 Canadian Assessment of Tomography for Childhood
Head injury rule (CATCH)
 Children's Head Injury Algorithm for the Prediction of
Important Clinical Events (CHALICE)
 Pediatric Emergency Care Applied Research Network
(PECARN)
 Only PECARN has been derived and validated.

28. CATCH
 Purpose: Identify high risk criteria 3
 Study
 4000 children including GCS 13
 4 high risk factors and 3 medium risk factors
 Sensitivity 98% for intermediate factors, 100% for high
risk
 Problems
 Requires 52% of pts undergo CT
 Not prospectively validated
3. Osmond MH, et al. CATCH: a clinical decision rule for the use of computed tomography in children
with minor head injury. CMAJ 2010; 182:341.

29. CATCHCT is required only for children with minor head injury* and any of one of
the following findgings:
High risk (need for neurologic intervention)
1. GCS < 15 at 2 hours after injury
2. Suspected open or depressed skull fracture
3. History of worsening Headache
4. Irritability on examination
Medium risk (brain injury on CT scan)
5. Any sign of basal skull fracture
6. Large, boggy hematoma of the scalp
7. Dangerous mechanism of injury (e.g.: MVC, fall from elevation > 3 ft or 5 stairs,
fall from bicycle with no helmet)
*Injury 24 hours associated with witnessed LOC, definite amnesia, witnessed
disorientation, persistent vomiting (> 1 episode) or persistent irritability (in
children < 2 years of age) in a pt with GCS 13-15

30. CHALICE
 Purpose: Identify high risk criteria 4
 Study
 22,772 children with head injuries
 10 hospitals in England
 281 ICH detected on CT scan
 14 high risk variables
 Sensitivity 98.6% and Specificity 87% for ICH
 For pts with GCS 13-15, sensitivity 97.6%
 Problems
 In a retrospective study, rate of head CT increased from 6.5 to 10%
with very few additional skull fx found.
 In another retrospective observation study, head CT rate increased
from 19 to 46% and missed six with intracranial injury.
4. Dunning J, et al. Derivation of the children’s head injury algorithm for the prediction of important clinical
events decision rule for head injury in children. Arch Dis Child 91: 885, 2006.

31. CHALICE
History Mechanism Physical Examination
Witnessed LOC > 5 min MVC > 40km/h or 25
MPH
GCS < 15 for < 1 year of
age
Amnesia > 5 min Fall > 3 m or 10 ft GCS <14 for >1 year of age
3 or more episodes of
emesis
High-velocity projectile Depressed or basilar skull
fracture
Traumatic Seizure Penetrating injury
Suspicion of NAT Tense fontanelle
Drowsiness Focal Neuro Deficit
Bruising, swelling,
laceration > 5 cm if < 1
year of age

32. PECARN
 Derived and validated prediction rule to decide when to forgo
head CT. 5
 Multicenter study- 25 EDs
 Among enrolled children (GCS 14-15, < 18 years old)
 < 2 years of age: 8502 in derivation, 2216 validation
 >=2 years of age: 25,283 in derivation, 641 in validation.
 ciTBI
 Death from TBI
 NSS intervention
 Intubation >24 hrs duration
 Hospital admission >= 2 nights
 CTs obtained in 37% (derivation) and 35% (validation) of pts
 Follow: Caregivers called at day 7 and 90
5. Kupperman, N, et al. Identification of children at very low risk of clinically-important brain
injuries after head trauma: a prospective cohort study. Lancet 374 (9696): 1160, 2009.

33. PECARN
Age Group Low-risk Criteria Sensitivity NPV
<2 years Normal Mental
Status
100% (86-100%) 100% (99.7-100%)
No scalp hematoma
except frontal
LOC < 5 sec
Nonsevere mech
No palpable skull fx
Normal behavior
>=2 years Normal mental
status
96.8% (89-100%) 99.95% (99.8-
100%)
No LOC
No vomiting
Nonsevere mech
No signs of basilar
skull fx
No severe headache

34. PECARN
 Results
 Prevalence of ciTBI was
approximately 1% in both
derivation and validation
cohorts
 Defined further risk
stratification
 Otherwise, may increase CT
usage
 Intermediate risk: 0.9%
(About 30% of all patients)
 High risk: >4%

35. PECARN
A- < 2 yrs old
B- >= 2 yrs old

36. PECARN
 Modified form of PECARN was externally validated 6
 High clinician satisfaction (96%)
 High adherence to rule (94%)
 Identified all 3 children with ciTBI at first visit
 Non-statistically significant increase of Head CT (7 to 8%)
 Benefits
 Gives physicians room for clinical judgment
 A tool for physicians to risk stratify
 Problems
 Very low rate of clinical significant head injury
 Lower bounds of 95% confidence intervals are low than other
adult head CT rules.
6. Bressan, S., et al. Implementation of Adapted PECARN Decision Rule for Children with Minor Head Injury in
the Pediatric Emergency Department. Academic Emergency Medicine. 19 (7); 801-807, 2012.

37. Disposition
 Asymptomatic infants/children
 If greater than 2-4 hrs postinjury, can d/c home.
 Can discharge if no suspicion of NAT, easily aroused with normal neuro exam, return
to baseline level of function, tolerating PO fluids, no extracranial injuries, reliable
caretaker.
 Return precautions: lethargy, irritability, focal deficits, vomiting in 24 hours.
 Intermediate risk
 Observation
 Unclear exact time but 4-6 hours is common
 Head CT
 > 1 risk factors or any in < 3 months
 High risk- Head CT and/or Neurosurgery
 Normal Head CT: Clinical judgment for obs vs admission
 Non-displaced Fracture (no ICH): NSS follow up
 ICH: NSS and admission

38. Moderate/Severe Brain Injury
 Moderate TBI: 10% of all head injuries
 Mortality < 20%
 Long term disability as high as 50%
 Severe TBI
 Mortality: ~40% (mostly in first 48 hours)
 Moderate recovery: < 10%
 75% of children with multiple trauma have TBI
 ~80% of all trauma deaths a/w severe brain injury
 TBI accounts for 95% of severe and fatal injuries.
 Mechanisms
 Children < 4 yrs old: fall accounted for 41%
 Adolescents: 43% from MVC
 <1 year old in ICU: 52% Assaulted

39. Pathophysiology
 Brain sensitive to ischemia and hypoxia
 Consumes 20% of total body oxygen and 15% of cardiac
output
 Changes in blood volume, pH, PO2, PCO2regulates
blood flow (O2 delivery and metabolism)
 Vasoconstriction occurs with
hypertension, hypocarbia, and alkalosis.
 Cerebral perfusion pressure
 Surrogate indicator for cerebral blood flow
 CPP = MAP - ICP

40. Pathophysiology
 Skull is a closed space with three intracranial
compartments.
 Brain parenchyma, CSF, intravascular blood
 When one increases, the others will decrease to
maintain ICP (Monro-Kellie Hypothesis)
 Normal ICP
 Adult/Older children: < 10- 15 mm Hg
 Children: 3-7 mm Hg
 Infants: 1.5- 6 mm Hg
 CPP normally > 60 mm Hg

41. Pathophysiology

42. Pathophysiology
 Primary injuries
 Contusions, hematomas, DAI, direct cellular damage,
tearing/shearing of tissues, loss of blood-brain barrier
 Secondary Injuries
 Downstream effects from primary injury
 Excessive glutamate released into presynaptic space activation of
postsynaptic receptors
 Flood of Ca2+ intracellularly
 Disrupts Na and K and normal function of cells.
 Mitochondria uptakes excess Ca Free radicals and more cellular
dysfunction.
 Leads to necrosis inflammation  apoptosis/membrane integrity
 cytotoxic edema and extracellular edema  increase in ICP 
compression and herniation.

43. Assessment Neurological assessment
 LOC
 Pupillary exam for size, reactivity, symmetry
 EOM
 Fundoscopic exam
 Brainstem reflexes (corneal and gag reflexes)
 DTR
 Response to pain
 Signs of herniation
 CN III nerve palsy
 Changes in resp pattern, pupil size,
vestibuloocular reflexes, posture.
 Cushing’s Triad

44. Treatment
 Prevent secondary insult
 Identify Treatable Mass Lesions
 Identify Other Life-Threatening Injuries

45. Treatment
 Secondary Insult- hypoxemia, hypotension, anemia, hyperglycemia,
hyperthermia, intracranial mass
 Single episode of hypotension or hypoxia a/w 150% increase in
mortality.
 Airway/Breathing
 Intubation (GCS < 8 or deteriorating)
 Cuffed tubes to prevent aspiration
 No nasotracheal intubation with midface trauma or basilar skull fractures
 Preinduction agents do not improve outcome.
 Induction: limited effect on ICP or MAP
 Etomidate, 0.3 mg/kg IV
 Propofol 1-3 mg/kg IV
 Ketamine 1.5-2.0 mg/kg IV 7
 Paralytic
 Succinylcholine 1-1.5 mg/kg IV
 Rocuronium 0.6-1 mg/kg IV
7. Filanovsky, Y., et al. Myth: Ketamine should not be used as an induction agent for intubation in
patients with head injury. CJEM. 12 (2):154-7. 2010.

46. Treatment
 Circulation
 In severe TBI, 1 hypotensive episode doubles mortality.
 Aggressive fluid resuscitation (isotonic solution)
 Maintain MAP > 80 mm Hg
 Relative Hypotension- Normal BP but not sufficient perfusion
 SBP < 100 mm Hg rarely associated with MAP > 80 mm Hg.
 Fix sources of bleeding on the external head
 Vasopressors to keep MAP at 80 mm Hg.
 Hypertension could be a sign of cushing’s reflex.
 Head positioning 30 degrees

47. Treatment
 Hyperglycemia
 Associated with poor outcomes
 In 1 study, for children < 14 years old going for emergent
craniotomy for TBI
 Perioperative hyperglycemia (glc > 200 mg/dL) found in 45%
of children
 A/w <4 years, GCS <=8, multiple traumatic lesions
 Hyperthermia- prevent and treat aggressively

48. ICP
 ICP > 20 mm Hg increases morbidity and mortality.
 Clinical Signs:
headache, nausea, vomiting, seizure, lethargy, Cushing’s
triad, agonal respirations
 Herniation
 Unilateral or bilateral pupillary
dilatation, hemiparesis, motor posturing, and/or
progressive neurological deterioration.

49. ICP- Treatment
 Mannitol
 lowers ICP; improves CBF, CPP and brain metabolism
 Free radical scavenger
 Expands plasma volume
 Diuretic so maintain euvolemia
 Hypertonic saline
 Bolus or infusion
 Reduces intracranial pressure.
 Adverse effects: rebound intracranial hypertension, central pontine
myelinolysis, SAH.
 Hyperventilation
 Not recommended as prophylactic intervention
 Reduces ICP and causes vasoconstriction. Decreased CBF and hypocapnia a/w
increased mortality.
 Keep PaCO2 at 35-40mm Hg and O2 sat > 95%
 If pending herniation, PCO2 30-35 mm Hg

50. ICP-Treatment
 Barbiturate Coma
 Not initiated in the ED
 Treats refractory intracranial hypertension in ICU.
 ICP monitoring recommended
 Treat seizures
 SZs raise ICP
 Prophylactic anticonvulsants reduced post-traumatic seizures
within first week, but do not improve long-term outcome.
 Prophylaxis is controversial, but experts suggest
anticonvulsant therapy for 1 week after seizure.
 Steroids- no role in TBI or increased ICP
 Burr hole- emergent treatment for epidural hematoma

51. Abusive Head Trauma
 In US, abusive head trauma (AHT) incidence in <2 years
old is 17 per 100,000 person-years
 Previous abuse noted in up to 60% of cases.
 Missed AHT in 31% of children
 Most often: Viral GE, influenza, accidental head trauma, “rule
out sepsis”
 Risk factors
 Infant: perinatal illness, birth defects, incessant crying, male
gender
 Family: Familial dysfunction (i.e.: drugs/ETOH), young
maternal age, family disruption/separation, history of abuse
in child or family members

52. AHT Workup
 Physical exam
 Retinal hemorrhages- 60-85% of abusive head injury
 Facial cutaneous bruising- linear strap marks, buttocks
bruising, 54% do not have bruising.
 C-spine injury- 4% of abusive head injury
 Evaluation
 Rule out coagulopathy- CBC, Coags
 Rule out other organ injury- Electrolytes, LFT, UA
 Rule out meningitis- CSF RBC/Xanothochromia (83% of
abusive head injury)
 Skeletal Survey X-ray
 Head CT
 MRI- follow up CT or asymptomatic but non-cranial injuries

53. Subdural Hematoma
 Blood accumulation between dura mater
and the arachnoid mater
 Mechanism
 Sudden acceleration-deceleration of brain
parenchyma tearing bridging veins
 Blood collects more slowly because venous.
 Classification
 Acute
 Subacute
 Chronic (> 2 weeks)

54. Subdural Hematoma
 Clinical Features
 A/w other brain and parenchymal injuries
 High risk populations: Elderly and alcoholics (atrophic brains) and children < 2
years old (NAT)
 Acute: Severe trauma + LOC (possible lucid period)
 Chronic: progressive AMS and behavior change
 SDH + long bone/posterior rib fx  NAT
 Strong correlation with NAT (50% of reviewed SDH cases a/w NAT)
 Can be a/w perinatal birth trauma (cranial sutures tearing dural veins)
 CT
 Crescent shaped lesions that cross suture lines
 Subacute SDH are isodense and harder to identify
 MRI
 Head CT IV contrast
 Chronic: hypodense (dark)
 Treatment: NSS  Obs vs surgery

55. Diffuse Axonal Injury
 Disruption of axonal fibers in the white matter
and brainstem by sudden deceleration.
 Mechanism: Blunt trauma and shaken baby
 Clinical Features
 Edema can develop quickly.
 AMS
 CT
 Classically: punctuate hemorrhagic injury along
grey-white junction of cerebral cortex and deep
structures of brain
 Can be normal
 Treatment
 Limited
 Prevent secondary injury by reducing edema and
limiting increases in ICP

56. Shaken Baby Syndrome
 Life threatening injury in children < 2 years
of age.
 Mechanism
 Rapid acceleration and rotation of cranium
 Impact on solid object  angular rotation
 Injuries
 Shearing injuries of intracranial
vessels, cervical spine injury, and intraocular
injury.
 Clinical signs
 Increased drowsiness, lethargy, decreased
feeding
 40% had no signs of external injury on initial
evaluation

57. Case Conclusion
 Taken to the OR for evacuation of L sided EDH with bone flap removed.
 L femur fracture treated ORIF
 Developed VAP with Acinetobacter and Enterobacter.
 Thalamic storms/dysautonomia
 Transferred to Children’s 3 weeks later.
 Taken back to the OR with plastics and NSS for scalp wound debridement and tissue rearrangement.
 Developed neutropenia 2/2 bactrim and seroquel.
 Extubated but had persistent fevers and had a tracheostomy placed 2/2 to respiratory distress.
 Plastics took pt to OR for completing skin graft over scalp.
 Pt transferred to floor and eventually weaned off ventilator for 2 weeks.
 Discharged home.

58. References
 Kirsch, TD, et al. Head Trauma in Adults and Children. In: Tintinalli, JE, ed.
Tintinalli’s Emergency Medicine- A Comprehensive Study Guide, 7th Edition.
China. The McGraw-Hill Companies, Inc. 2011. Chapter 254
 Tintinalli, JE. Minor Head Injury in Infants and Children. In: Tintinalli, JE, ed.
Tintinalli’s Emergency Medicine- A Comprehensive Study Guide, 7th Edition.
China. The McGraw-Hill Compaines, Inc. 2011. Chapter 132.
 Marx JA, Hockberger RS, Walls RM, et al., eds. Rosen's Emergency Medicine:
Concepts and Clinical Practice. Philadelphia, PA: Mosby/Elsevier; 2014.
 UpToDate
 Bressan, S., et al. Implementation of Adapted PECARN Decision Rule for
Children With Minor Head Injury in the Pediatric Emergency Department.
Academic Emergency Medicine. 2012; 19:801-807.
 Hennelly, KE., et al. Pediatric Traumatic Brain Injury and Radiation Risks: A
Clinical Decision Analysis. The Journal of Pediatrics. 2012;162:392-397.
 Schonfeld, D., et al. Effect of Duration of Emergency Department Observation
on Computed Tomography Use in Children With Minor Blunt Head Trauma.
Annals of Emergency Medicine. 2013;62:597-603.