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Hypothermia for Hypoxic Ischemic Encephalopathy. Mitchell Imm, M.D. What now?. Meta-analysis (3 randomized clinical trials) shows that mild hypothermia is associated with a significant reduction in death or severe disability

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What now
What now?

  • Meta-analysis (3 randomized clinical trials) shows that mild hypothermia is associated with a significant reduction in death or severe disability

    Edwards and Azzopardi. “Therapeutic Hypothermia Following Perinatal Asphyxia.” Archives of Disease in Childhood: Fetal and Neonatal ed. 2006.

  • What form: Selective head cooling vs. Whole Body cooling?

  • What degree of hypothermia provide the most neuroprotection?

  • What is the optimum duration of hypothermia?

  • Is it effective outside of 6 hours?

  • Is it protective for infants with severe HIE?

  • Will the benefits endure when the child reaches school age?


Hypoxic ischemic encephalopathy
Hypoxic Ischemic Encephalopathy

  • Causedby impaired cerebral blood flow

  • Moderate to severe HIE occurs 2-4/1000 live births

  • 10% mortality rate for newborns with moderate HIE

  • 60% mortality rate for newborns with severe HIE.

  • 25-30% survivors with moderate HIE have long term disabilities

  • Nearly 90% survivors with severe HIE have long term disabilities



Hypoxic ischemic insult
Hypoxic Ischemic Insult

  • Usually cause by interruption in placental blood flow

  • Subsequent interruption of cerebral blood flow

  • fetal response

    • Cerebral vasodilatation

    • Redistribution of organ blood flow

    • Loss of cerebral autoregulation


Birth asphyxia
Birth Asphyxia

  • Condition of impaired gas exchange that leads to hypoxemia and hypercapnia

  • Fetal acidosis: umbilical arterial pH <7.0 and base deficit >=12

  • Early onset of moderate-severe encephalopathy

  • Spastic quadriplegic or dyskinetic CP

  • Exclusion of other identifiable etiologies

  • Other nonspecific criteria

    • Sentinel hypoxic event before or during labor

    • Sustained fetal bradycardia or other signs of non-reassuring fetal status

    • APGAR 0-3 beyond 5 minutes

    • Multi-organ failure within 72 hours

    • Early imaging studies showing acute, non-focal cerebral abnormality

      • From ACOG Task Force in Neonatal Encephalopathy and Cerebral Palsy, 2003


Risk factors
Risk Factors

  • Severe preecclampsia

  • Placental abruption

  • Multiples

  • Antepartum hemorrhage

  • IUGR

  • Malpresentation

  • Cord prolapse

  • Stat C-section

  • Maternal fever



Primary energy failure
Primary Energy Failure

  • Decreased high energy phosphate compounds, e.g. phosphocreatine and ATP

  • Failure of ion pumps leading to Na, K, Ca ionic gradient disturbances

  • Mitochondrial dysfunction

  • Glutamate release

  • NMDA receptor overstimulation



Reperfusion
Reperfusion

  • Return of cerebral blood flow

  • Normal blood pressure

  • Normal intracellular pH

  • Transient improvement of cytotoxic edema

  • No seizures


Latent phase
Latent Phase

  • Depressed EEG activity

  • Recovery of the mitochondria



Secondary energy failure
Secondary Energy Failure

  • 6-24 hours after insult

  • Decreased high energy phosphates

  • Similar pathways as Primary Energy failure

  • Seizures

  • Cytotoxic edema

  • Excitotoxins

  • Cell death


Secondary energy failure1
Secondary Energy Failure

“The severity of secondary phase energy failure is strongly correlated with adverse neurodevelopmental outcomes at 1 and 4 years of age.”

RA Polin, TM Randis, R Sahni. “Systemic Hypothermia to Decrease Morbidity of Hypoxic-ischemic Brain Injury.” Journal of Perinatology. 2007


Mechanisms of cell injury
Mechanisms of Cell Injury

  • Failure of ion pumps

  • Influx of Na, Ca, and water

  • Glutamate release and subsequent activation of NMDA glutamate receptors

  • Further increase in intracellular Ca

  • Activation of lipases, proteases, endonulceases, phospholipases

  • NO synthesis

  • Oxygen free radical synthesis

  • Free fatty acid peroxidation

  • Inflammatory mediators


Cell death
Cell Death

  • Necrosis

    • organelle disruption

    • plasma membrane disruption and rupture

    • cell swelling

  • Apoptosis

    • programmed cell death

    • cell shrinkage

    • nuclear pyknosis

    • chromatin condensation

    • genomic fragmentation


Apoptosis
Apoptosis

  • Caspase activation

    • cysteine proteases

    • cleavage of inhibitor of caspase-activated DNase

    • Inactivates DNA repair enzyme

    • activation of caspase-activated DNase

    • DNA fragmentation and chromatin condensation

  • Apoptosis inducible factor

    • independent of caspase

    • translocates to the nucleus

    • leads to DNA fragmentation and chromatin condensation


Patterns of brain injury
Patterns of Brain Injury

  • Most common area of injury occurs in parasagittal cortex (watershed areas) and basal ganglia and thalamus.

  • Parasagittal injury caused by prolonged or partial asphyxia and causes cognitive impairments

  • Basal ganglia/thalamus injury caused by acute, near total asphyxia and presents with more seizure activity. Long term sequelae are cognitive defects, rigidity, seizures, motor speech impairment


Modified sarnat staging of hie
Modified Sarnat Staging of HIE

  • Level of consciousness

  • Activity

  • Neuromuscular control

  • Complex/primitive reflexes

  • Autonomic function

  • Seizures


Sarnat stage 1 mild
Sarnat Stage 1 (mild)

  • Hyper-alert

  • Active

  • Normal muscle tone

  • Mild distal flexion

  • Overactive stretch reflexes

  • Weak suck

  • Strong Moro

  • Slight tonic neck

  • Mydriasis

  • Tachycardia

  • No seizures

  • Neuro exam usually normalizes by 3-4 days

  • No long term sequelae


Sarnat stage 2 moderate
Sarnat Stage 2 (moderate)

  • Lethargic or obtunded

  • Decreased activity

  • Mild hypotonia

  • Strong distal flexion

  • Overactive stretch reflexes

  • Weak or absent suck

  • Weak or incomplete Moro

  • Strong tonic neck

  • Miosis

  • Bradycardia

  • Focal or multi-focal seizures


Sarnat stage 3 severe
Sarnat Stage 3 (severe)

  • Stupor or coma

  • No activity

  • Flaccid muscle tone

  • Intermittent decerebration

  • Decreased or absent stretch reflexes

  • Absent suck

  • Absent Moro

  • Absent tonic neck

  • Variable pupils; fixed, deviated, non-reactive, and dilated

  • Variable heart rate

  • Uncommon seizures


Other studied treatments
Other Studied Treatments

  • Mannitol

  • Glucocoticoids

  • Phenobarbital

  • Calcium Channel Blockers

  • Magnesium Sulfate

  • Allopurinol

  • Resuscitating with FiO2 0.21 instead of 1.0

  • Superoxide dismutase


Hypothermia for hie
Hypothermia for HIE

  • Miller et al. “Hypothermia in the Treatment of Asphyxia Neonatorum.” 1964

  • Gluckman et al. “Selective Head Cooling with Mild Systemic Hypothermia after Neonatal Encephalopathy Multicenter Randomized Trial.” Lancet. 2005

  • Shankaran et al. “Whole Body Hypothermia for Neonates with Hypoxic-Ischemic Encephalopathy.” New England Journal of Medicine. 2005.


Hypothermia for hie1
Hypothermia for HIE

  • in animal models temperature reductions of 2-5 degrees C provided neuroprotection

  • Impacts multiple pathways to brain injury

  • Affecting excitatory amino acids, brain metabolism, cerebral blood flow, nitric oxide production, apoptosis


Selective head cooling
Selective Head Cooling

  • N=234 randomized. 218 subjects were evaluated at 18 months

  • 07/1999 to 01/2002

  • Cool cap placed within 6 hours (avg. 4.3 hours of life)

  • Used the Cool Cap from Natus Medical Incorporated. http://www.natus.com

  • Infants randomized to normothermic control group (rectal temp 37 degrees Celsius) or hypothermic treatment group (rectal temp 34 degrees Celsius) for 72 hours




Selective head cooling3
Selective Head Cooling

  • Follow up @ 18 months for a neurodevelopmental exam; height, weight, head circumference measurements; Bayley-II psychometric testing; audiology assessment; vision assessment

  • Primary Outcome measures: Mortality and Severe Neurodevelopmental Disability (Gross Motor Function impairment level 3-5, Bayley mental scale<70, bilateral cortical visual impairment)


Selective head cooling4
Selective Head Cooling

  • entry criteria

    • At least 36 weeks gestation

    • APGAR <5 @ 10 min, or

    • Continued resuscitation, or

    • Severe acidosis ph<7, base deficit >= 16 on an umbilical cord blood sample or ABG/VBG done within 60 minutes of birth

    • Then, assessed for moderate or severe encephalopathy using the modified Sarnat

    • Then, aEEG showing moderate or severe background activity and/or seizures


Normal aeeg
Normal aEEG

Upper margin of band of aEEG activity above 10 uV and lower margin of band of aEEG activity above 5 uV


Moderately abnormal aeeg
Moderately abnormal aEEG

Upper margin of band of aEEG activity above 10 uV and lower margin below 5 uV.


Severely abnormal aeeg
Severely Abnormal aEEG

Upper and lower margin of band of aEEG activity below 10 uV


Seizures on aeeg
Seizures on aEEG

sudden increase in voltage accompanied by narrowing of the band of aEEG activity and followed by a brief period of suppression


Selective head cooling5
Selective Head Cooling

  • Adverse Events

    • Overall there was no statistically significant difference between the treatment and control groups, except for:

    • Minor cardiac arrhythmia

      • 9% vs. 1%

      • Mild sinus bradycardia

    • Scalp edema

      • 21% of treatment subjects

      • Resolved without any intervention after Cool Cap removed


Results

Treatment group

108 subjects

45% (49) favorable outcome

55% (59) unfavorable outcome

Death 33%

Severe motor disability 19%

Control group

110 subjects

34% (37) favorable outcome

66% (73) unfavorable outcome

Death 38%

Severe motor disability 31%

Results

No significant difference in rates of death or severe disability at 18 months (p=0.10)


Results1
Results

  • Infants with moderate aEEG abnormalities (N=172) there was a significant reduction in death or severe disability @ 18 months (48% vs. 66%, p=0.02)

  • Infants with severe aEEG abnormalities (N=46) there was no significant difference (68% vs. 79%, p=0.5)


Conclusions
Conclusions

“Although induced head cooling is not protective in a mixed population of infants with neonatal encephalopathy, it could safely improve survival without severe neurodevelopmental disability in infants with less severe aEEG changes.”


Whole body hypothermia
Whole Body Hypothermia

  • N=208 (239 eligible)

  • 07/2000 to 05/2003

  • Patients enrolled by 6 hours of life (avg. 5 hours 2 min of life)

  • Subject randomized to hypothermic treatment group (esophageal temp 33.5 degrees C) for 72 hours vs. normothermic control group


Methods
Methods

  • Treatment group placed on infant blanket cooled to 5 degrees C. Esophageal temperatures were monitored and set to 33.5 degrees C by the servomechanism. Abdominal wall temperatures monitored.

  • Esophageal and abdominal wall temp monitored every 15 min for 4 hours, every hour for 8 hours, then every 4 hours

  • Rewarming 0.5 degrees C every hour till infant’s temp was 36.5 degrees C after 72 hours of hypothermia



Follow up
Follow up

  • Primary outcome: death or disability (moderate or severe)

  • Evaluated at 18-22 months for neuromotor disability, Bayley II, growth, vision assessment, hearing assessment

  • Severe disability defined as Bayley Mental Development Index<70, GMFCS grade 3-5, hearing impairment requiring hearing aids, blindness

  • Moderate disability Bayley MDI 70-84 plus 1 of the following: GMFCS grade 2, epilepsy, hearing impairment without amplification


Entry criteria
Entry Criteria

  • At least 36 weeks gestation

  • Acidosis pH<7, base deficit >=16 on an umbilical cord blood sample or 1 hour blood gas, or

  • If pH 7.01-7.15, base deficit 10-15.9, and blood gas unavailable, there must be acute perinatal event and 10 min APGAR <= 5 or assisted ventilation for >= 10 min

  • Then, neurological examination to determine severity of encephalopathy using the modified Sarnat


Sarnat stage 2 moderate1
Sarnat Stage 2 (moderate)

  • Lethargic or obtunded

  • Decreased activity

  • Mild hypotonia

  • Strong distal flexion

  • Overactive stretch reflexes

  • Weak or absent suck

  • Weak or incomplete Moro

  • Strong tonic neck

  • Miosis

  • Bradycardia

  • Focal or multi-focal seizures


Sarnat stage 3 severe1
Sarnat Stage 3 (severe)

  • Stupor or coma

  • No activity

  • Flaccid muscle tone

  • Intermittent decerebration

  • Decreased or absent stretch reflexes

  • Absent suck

  • Absent Moro

  • Absent tonic neck

  • Variable pupils; fixed, deviated, non-reactive, and dilated

  • Variable heart rate

  • Uncommon seizures


Exclusion criteria
Exclusion Criteria

  • Unable to enroll by 6 hours of age

  • Major congenital anomalies

  • Severe growth restriction (BW<1800 grams)

  • Refusal of consent

  • Moribund infants for whom no further treatment was planned


Adverse events
Adverse Events

  • no significant difference between treatment and control groups, except for sinus bradycardia and skin changes

  • Mean HR 109 for treatment group vs. 140 for control group

  • Skin changes include erythema, sclerema, cyanosis, subcutaneous fat necrosis (4/102 infants)


Results2

Treatment group

102 subjects

56% (57) favorable outcome

44% (45) unfavorable outcome

Death 24% (24)

Control group

103 subjects

38% (39) favorable outcome

62% (64) unfavorable outcome

Death 37% (38)

Results

Significant difference in rates of death or moderate to severe disability at 18-22 months (p=0.01).


Results3
Results

  • There was no significant difference between treatment and control groups when basing it on the degree of encephalopathy (moderate 32% vs. 48%, p=0.09; severe 72% vs. 85%, p=0.24)

  • There was no significant difference when comparing the incidence of disabling CP, blindness, severe hearing impairment, Bayley Mental Development Index, Bayley Psychomotor Development Index


Conclusion
Conclusion

“As compared with the usual care, whole-body cooling to an esophageal temperature 33.5 degrees C initiated within the 1st 6 hours after birth and continued for 72 hours reduced the rate of death or moderate or severe disability in term newborns with encephalopathy in this study.”


HYPOTHERMIA FOR HYPOXIC ISCHEMIC ENCEPHALOPATHY

EFFECT ON OVERALL MORTALITY

Increased

Risk Difference

Decreased

Risk

STUDY

( 95% CI )

0.2

0.5

1.0

2.0

GUNN 1998

-0.06 (-0.35, 0.22)

SHANKARAN 2002

-0.08 (-0.47, 0.32)

EICHER 2005

-0.11 (-0.34, 0.12)

GLUCKMAN 2005

-0.05 (-0.18, 0.08)

SHANKARAN 2005

-0.12 (-0.25, 0.00)

SHAO

-0.11 (-0.24, 0.02)

TYPICAL ESTIMATE

-0.09 (-0.16,-0.02)

0.2

0.5

1.0

2.0

SOLL 2006

Relative Risk and 95% CI


HYPOTHERMIA FOR HYPOXIC ISCHEMIC ENCEPHALOPATHY

EFFECT ON DISABILITY OR DEATH

Risk

Increased

Risk Difference

Decreased

STUDY

( 95% CI )

0.2

0.5

1.0

2.0

4.0

GUNN 1998

0.08 (-0.26, 0.42)

GLUCKMAN 2005

-0.12 (-0.25, 0.01)

SHANKARAN 2005

-0.16 (-0.30,-0.03)

TYPICAL ESTIMATE

-0.12 (-0.21,-0.04)

0.2

0.5

1.0

2.0

4.0

Relative Risk and 95% CI

SOLL 2006


What now1
What now?

  • Meta-analysis (3 randomized clinical trials) shows that mild hypothermia is associated with a significant reduction in death or severe disability

    Edwards and Azzopardi. “Therapeutic Hypothermia Following Perinatal Asphyxia.” Archives of Disease in Childhood: Fetal and Neonatal ed. 2006.

  • What form: Selective head cooling vs. Whole Body cooling?

  • What degree of hypothermia provide the most neuroprotection?

  • What is the optimum duration of hypothermia?

  • Is it effective outside of 6 hours?

  • Is it protective for infants with severe HIE?

  • Will the benefits endure when the child reaches school age?


HYPOTHERMIA FOR THE TREATMENT OF

HYPOXIC ISCHEMIC ENCEPHALOPATHY

From the NICHD Hypothermia Workshop

Implications for clinical practice:

“Based on the available evidence and the known gaps in knowledge, at the current time, therapeutic hypothermia should be deemed as an evolving therapy the long-term safety and efficacy of which need to be established.”

“…The known heterogeneity in neuropathological changes after perinatal HIE combined with potential regional heterogeneity of treatment effects will lead to marked differential effects on outcomes among survivors of HIE (e.g. physical disability versus cognitive deficits). This underscores the need for longer term follow up of all HIE infants undergoing any treatment.”


HYPOTHERMIA FOR THE TREATMENT OF

HYPOXIC ISCHEMIC ENCEPHALOPATHY

Implications for clinical practice (cont):

“Therapeutic hypothermia, if offered, should be used only under published protocols as used in the Cool Cap (selective hypothermia) and NICHD trials (whole body hypothermia), or as part of ongoing controlled trial(s) of induced hypothermia for HIE, with appropriate follow up mechanisms…..”

NICHD Hypothermia Workshop


HYPOTHERMIA FOR THE TREATMENT OF

HYPOXIC ISCHEMIC ENCEPHALOPATHY

Implications for clinical practice:

“The ongoing TOBY, ICE, and other hypothermia trials need to be completed to enhance our understanding of the role of hypothermia in perinatal asphyxia. Scientists planning future trials may wish to consider protocol designs similar to the ones already implemented so that specific questions can be answered and the results can systematically compared to the existing experience.”

“There is an urgent need for national and international registries to enable ongoing data collection of data on perinatal encephalopathy, its treatments, and long-term outcomes.”

“Institutions offering hypothermia in non-research settings also need to document clinical data in a systematic way, and ensure long-term follow-up of treated infants using standardized follow-up protocols developed by centers conducting hypothermia trials and preferably submit information to such registries.”

NICHD Hypothermia Workshop


Pending studies
Pending Studies

  • TOBY (Total Body Cooling Trial): N=325. Submitted for publication in 2009

  • ICE (Infant Cooling Evaluation): N=204. Study stopped due to lack of equipoise.

  • Neo nEuro Network: N=121. Study stopped due to lack of equipoise.


“even if the three trials named previously with 650 infants did not show any positive effect the RR would still have a CI less than 1.0 and the NNT would increase to 15.”

Dr. Marianne Thoresen


Total body cooling protocol
Total Body Cooling Protocol infants did not show any positive effect the RR would still have a CI less than 1.0 and the NNT would increase to 15.”


Inclusion criteria
Inclusion Criteria infants did not show any positive effect the RR would still have a CI less than 1.0 and the NNT would increase to 15.”

  • ≥ 36 weeks gestation

  • ≥ 1800 grams

  • ≤ 6 hours old

  • pH ≤ 7 or base deficit ≥ 16

  • Seizures

  • History of acute perinatal event

  • APGAR ≤ 5 at 10 minutes or Continued ventilation for ≥ 10 minutes

  • Abnormal neurological exam


NO infants did not show any positive effect the RR would still have a CI less than 1.0 and the NNT would increase to 15.”

36 weeks gestation, ≥ 1800 grams, ≤ 6 hours old

NOT ELIGIBLE

Blood gas pH of 7.0 or less

- cord gas (venous/arterial), OR

- any postnatal blood gas within the

first hour of life (ABG/CBG/VBG)

OR

Base deficit of 16 mEq/L or more

Cord gas or any postnatal blood gas in the first hour of life

pH of 7.01 to 7.15

or

Base Deficit of 10 to 15.9 mEq/L

NO

NO

YES

NO

History of an Acute Perinatal Event

Examples: abruptio placenta, cord prolapse, variable or late decelerations

And either:

10 minuteVentilation initiated

APGAR or at birth and continued

Score of ≤ 5for at least 10 minutes

YES

SEIZURES?

YES

YES

NO

NEURO EXAM

ELIGIBLE FOR COOLING

YES

NO

At least one sign in any 3 of 6 categories

Category Moderate Encephalopathy Severe Encephalopathy

1. Level of consciousness Lethargic Stupor/coma

2. Spontaneous activity Decreased activity No activity

3. Posture Distal flexion Decerebrate

Full extension

4. Tone Hypotonia (focal/general) Flaccid

5. Primitive reflexes

Suck Weak Absent

Moro Incomplete Absent

6. Autonomic system

Pupils Constricted Skew dev, dilated

Non-reactive

Heart Rate Bradycardia Variable HR

Respirations Periodic breathing Apnea


Exclusion criteria1
Exclusion Criteria infants did not show any positive effect the RR would still have a CI less than 1.0 and the NNT would increase to 15.”

  • > 6 hours old

  • Major congenital abnormality

  • Known chromosomal abnormality

  • Severe growth restriction (weight < 1800 grams)

  • Moribund infants


Target vital signs
Target Vital Signs infants did not show any positive effect the RR would still have a CI less than 1.0 and the NNT would increase to 15.”

  • Temperature 33.5°C ± 0.5°C

  • MABP 45-65 mmHg

  • O2 Sat 93-98%

  • PCO2 45-58 mmHg (analyzed at 37°C, true value is lower by 0.83)

  • PO2 60-100 mmHg


Equipment
Equipment infants did not show any positive effect the RR would still have a CI less than 1.0 and the NNT would increase to 15.”

  • Blanketrol III

  • Pediatric cooling blanket and hoses

  • 7 L sterile water

  • Esophageal and rectal temperature probes

  • BRAINZ aEEG monitor

  • aEEG low impedence needle leads

  • aEEG hydrogel lead


Pre cooling phase
Pre-cooling Phase infants did not show any positive effect the RR would still have a CI less than 1.0 and the NNT would increase to 15.”

  • AVOID HYPERTHERMIA. Keep temperature 36-37°C

  • Foley

  • aEEG leads placement

  • Arterial access

  • Venous access

  • Do not let these steps delay initiation of hypothermia


Cooling phase
Cooling Phase infants did not show any positive effect the RR would still have a CI less than 1.0 and the NNT would increase to 15.”

  • Place esophageal and rectal temperature probe. CXR to confirm proper placement of esophageal probe

  • Place infant on cooling blanket

  • Set target temperature on Blanketrol III to 33.5°C

  • Push Set Gradient Variable ± 10°C

  • Cool for 72 hours


Vital sign monitoring
Vital Sign Monitoring infants did not show any positive effect the RR would still have a CI less than 1.0 and the NNT would increase to 15.”

  • Vital signs every 15 min till set temperature is reached

  • Time 0 begins once patient’s temperature is 33.5°C

  • Hours 0-2: vital signs every 15 min

  • Hours 2-4: vital signs every 30 min

  • Hours 4 to 72: vital signs every hour


Skin integrity checks
Skin Integrity Checks infants did not show any positive effect the RR would still have a CI less than 1.0 and the NNT would increase to 15.”

  • Skin assessed every hour

  • Sclerema Neonatorum: generalized hardening of the skin and soft tissue

  • Scalp swelling

  • Erythema

  • Cyanosis

  • Exaggerated acrocyanosis

  • Waffling

  • Shift baby’s position slightly on the blanket to prevent severe waffling. If baby is too unstable, simply emptying and refilling the cooling blanket may suffice


Baseline lab schedule
Baseline Lab Schedule infants did not show any positive effect the RR would still have a CI less than 1.0 and the NNT would increase to 15.”

  • Admission: CBC, CMP, Coags, Mg, Phosphorus, Direct Bilirubin, GGT, Blood gas

  • Hour 12: blood gas, iCa, glucose

  • Hour 24: blood gas, iCa, CMP, Mg, Phosphorous, Coags, CBC

  • Hour 36: blood gas, iCa, glucose

  • Hour 48: blood gas, iCa, glucose, BMP, Mg, Phosphorus, CBC

  • Hour 60: blood gas, iCa, glucose

  • Hour 72: blood gas, iCa, glucose, RT K+, CMP, Phosphorus, Mg, Coags


Alterations during hypothermia
Alterations during Hypothermia infants did not show any positive effect the RR would still have a CI less than 1.0 and the NNT would increase to 15.”

  • Sinus Bradycardia: HR reduced by 14 bpm per 1°C drop in temp

  • Diuresis due to mitigation of ADH

  • Decrease platelet count 10-39%

  • Prolonged coagulation studies, which may be a physiologic response to slower, stickier blood flow

  • Shivering


Alterations during hypothermia1
Alterations during Hypothermia infants did not show any positive effect the RR would still have a CI less than 1.0 and the NNT would increase to 15.”

  • Hypokalemia: This is NOT a true loss in total body K+ but rather an intra-cellular shift of K+. K+ will shift extra-cellularly upon rewarming.

  • Hyperglycemia: due to decreased insulin release and decreased glucose utilization

  • Hypomagnesemia

  • Hypophosphatemia

  • Hypocalcemia


Alterations during hypothermia2
Alterations during Hypothermia infants did not show any positive effect the RR would still have a CI less than 1.0 and the NNT would increase to 15.”

  • Drug metabolism decreased, especially drugs metabolized by liver, eg. phenobarbital, vecuronium, morphine

  • Shivering

  • Hypocapnia: 4% reduction in pCO2 per 1°C drop in temp

  • Thicker respiratory secretions requiring more frequent suctioning and may increase risk of pulmonary infection


Rewarming
Rewarming infants did not show any positive effect the RR would still have a CI less than 1.0 and the NNT would increase to 15.”

  • Gradually raise baby’s temperature 0.5°C per hour

  • Place a pillow under the baby’s head

  • Each hour increase the Set Point Temp on the Blanketrol III by 0.5°C till 36.5°C is reached

  • Turn off Blanketrol III. Remove esophageal probe

  • Turn on radiant warmer and set servo temperature to 36.5°C

  • Keep baby’s temperature 36 to 36.5°C for the next 24 hours

  • Babies can easily become hot after hypothermia


Vital signs and labwork
Vital Signs and Labwork infants did not show any positive effect the RR would still have a CI less than 1.0 and the NNT would increase to 15.”

  • Vital signs checked every 30 minutes till target temperature reached

  • Hour 1: Blood gas, iCa, glucose, RT K+

  • Then blood gas, iCa, glucose, RT K+ every 2 hours

  • When 36.5°C is reached, check blood gas, iCa, glucose, BMP, Mg, phosphorus, CBC, Coags

  • 24 hours after completion of rewarming, check blood gas, iCa, glucose, CMP, Mg, phosphorus, Direct bilirubin, GGT


Changes with rewarming
Changes with Rewarming infants did not show any positive effect the RR would still have a CI less than 1.0 and the NNT would increase to 15.”

  • Seizures

  • Hypotension: usually secondary to hypovolemia

  • Hyopglycemia

  • Watch for Hyperkalemia

  • Drug metabolism improves. Dosages may need to be increased to pre-cooling levels

  • Stools may be fatty

  • Apnea


Quality assurance
Quality Assurance infants did not show any positive effect the RR would still have a CI less than 1.0 and the NNT would increase to 15.”

  • Patient’s temperature range

  • Onset of hypothermia

  • Mortality

  • 18 month neurodevelopmental outcome

    • f/u with Dr. Del Angel

  • Infection

  • Skin Integrity


Transport
Transport infants did not show any positive effect the RR would still have a CI less than 1.0 and the NNT would increase to 15.”

  • Criteria for referring hospitals

    • APGAR ≤ 5 at 10 minutes

    • Need for continued assisted ventilation past 10 minutes

    • Acidosis in the 1st hour of life (pH ≤ 7 or base deficit ≥ 16)

    • Seizures

  • Avoid hyperthermia. Monitor temperatures every 30 minutes. Keep temperature between 36-37°C (96.8 to 98.6°F)

  • Can we get the patient hypothermic before 6 hours of life?


Late onset hypothermia trials
Late Onset Hypothermia Trials infants did not show any positive effect the RR would still have a CI less than 1.0 and the NNT would increase to 15.”

  • University of Texas Southwestern Medical Center at Dallas

    Contact: Pablo J. Sanchez, MD  214-648-3753    

    Contact: Nancy A. Miller, RN     214-648-3780        

    Principal Investigator: Pablo J. Sanchez, MD

  • University of Texas Health Science Center at Houston

    Contact: Kathleen A. Kennedy, MD MPH     713-500-6708

    Contact: Georgia E. McDavid, RN     713-500-5734      

    Principal Investigator: Kathleen A. Kennedy, MD MPH            

    Principal Investigator: Jon E. Tyson, MD MPH

  • http://clinicaltrials.gov/show/NCT00614744

  • Entry Criteria: age 6 to 24 hours old

  • Exclusion Criteria: any infant with a core temp < 34°C for >1 hour


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