1
5
neo.nEuro.network
10
Study protocol:
Induced systemic hypothermia in asphyxiated new-born
infants: a randomized, controlled, multicenter study
15
Appendix 1:
Procedures and definitions for neurological assessment,
aEEG and EEG assessment
Appendix 2:
Scientific basis for inclusion criteria, classification into subgroups and sample size calculations
Appendix 3:
Specifications for cooling mattress and aEEG device
Appendix 4:
Monitoring schedule
Appendix 5:
Case Record Form
20
25
30
35
Principal Investigator and Organizer:
Simbruner G, M.D., Professor of Pediatrics
Division Neonatology, University Childrens´s Clinic,
Ludwig-Maximilians University, Munich
Lindwurmstraße 4, D - 80337 Munich, Germany
Fax : + 49 89 5160 - 4419 ;
e-mail > simbruner@kk-i.med.uni-muenchen.de
40
Status:
3 May 2000
2
45
Study protocol :
Induced systemic hypothermia in asphyxiated new-born infants:
a randomized, controlled, multicenter study.
________________________________________________________________
50
55
Study Group
Participants in Germany and other European Countries within the framework of the
”neo-nEuro-network” (abbreviated n.n.n), an non-juridal association of neonatologists
interested in neurological and neuro-intensive care investigations.
60
Prinicipal Investigator:
Simbruner G, Division Neonatology, Ludwig-Maximilians University, Munich
Fax : + 49 89 5160 - 4419 ; e-mail > simbruner@kk-i.med.uni-muenchen.de
65
70
75
80
Scientific Committee of the nnn Hypothermia Study:
Blennow M, Huddige Hospital , Huddige, Sweden,
Gaus W, Univ Ulm, Ulm, Germany
Greisen G, Univ Copenhagen, Copenhagen, Denmark
Obladen M, Charite, Humboldt Univ, Berlin, Germany
Pohlandt F, Univ Ulm, Ulm, Germany
Simbruner G, LMU, Munich,Germany
Thoresen M, Univ Bristol, Bristol , UK
Zupan V, Univ Paris, Paris, France
Biometry:
W. Gaus, Department of Biometry and Medical Documentation
University of Ulm, Germany
Fax: +49 731 50-26902; e-mail: wilhelm.gaus@medizin.uni-ulm.de
Regional co-ordinators (Status 12 April, 2000):
Copenhagen, Denmark: Gorm Greisen
Munchen, Germany: Georg Simbruner
Paris, France: Veronique Zupan
85
90
Acknowledgement :
We thank the principal investigator Peter D Gluckman, Auckland, New Zealand of the
Olympic Medical Brain Cooling Trial and Olympic Medical for providing a copy of that
protocol. Inclusion and exclusion criteria and the primary endpoint is identical in the two
protocols. The brain cooling trial uses a cooling cap and a target body temperature of
34.5C whereas we will use systemic cooling to 33.5C and all patients receive morphine for pain and sedation. We think that the results from the two trials can add up to
3
95
document a potential benefit of hypothermia as well as suggest a difference between
the two approaches. I thank Professors Azzopardi D and Edwards DA for also providing
insight into their study protocol.
Synopsis
100
105
110
115
This randomized, controlled multicenter study aims to determine whether inducing systemic hypothermia in birth-asphyxiated new-born infants born at term increases the
chance of survival without severe neurodevelopmental handicap. Secondary objectives
are to determine whether the treatment benefit is greater in milder rather than more severe asphyxia, and whether systemic hypothermia is associated with significant sideeffects.
New-born infants with a gestational age of > 36 weeks , asphyxiated at birth, who show
evidence of encephalopathy and who have abnormal EEG within 6 hrs of postnatal age,
will be randomized to hypothermia or to normothermia. Hypothermia (target rectal temperature 33.5°C) will be induced by a cooling matters, perfused with water. Hypothermia
will be maintained for 72 hours. Infants in both groups will receive morphine at a sedative and analgesic dosage.
Neurological assessment will be done at 7 days, 6 and 18 months. Further, at
18 months the Griffith General Quotient will be assessed. The primary outcome is (1)
death, or (2) inability to sit unsupported, or (3) Griffith GQ < 85, or (43) bilateral cortical
blindness at 18 months or a combination thereof. The statistical analysis will examine
whether the hypothermia and control group differ in their proportion of infants surviving
without disability .
120
Background
Ethical considerations.
125
130
135
Severe birth asphyxia results in brain damage and death or lifelong handicap. The scientific community so far failed to provide an effective protective or therapeutic intervention.
Controlled mild hypothermia is the best candidate for a post-asphyxia intervention. Hypothermia has been proven effective in several animal species.
Extensive clinical experience with short term, deep hypothermia exists from heart surgery practice. Some clinical experience exists with long-term moderate hypothermia. Although hypothermia may have side effects, even if serious, they are likely to be acute,
whereas the benefits are likely to be long term.
It is therefore reasonable to proceed to a randomized controlled trial. A trial of selective
head cooling is under way in New Zealand, USA, Canada and the UK. The present
protocol is sufficiently similar and sufficiently different to the Olympic Medical Head
Cooling Trial to be likely to add significantly to the evidence provided by that study.
The major ethical concern is the limited possibility to obtain truly informed, free consent
by the parents. There is no solution to this problem. It will be the duty of the investiga-
4
140
tors to remain sensitive to parental wishes, to obtain the best possible consent, and to
offer a high level of information to the parents throughout the study.
Epidemiolgy.
145
The incidence of asphyxiated full-term infants still ranges between 2 and 4 infants per
1000 deliveries in high income countries (1, 2) and may be significantly higher in low
income countries. Birth asphyxia results in longterm neurological sequelae in up to 20%
of infants, if moderate and in up to 100% of infants, if severe. Birth asphyxia causes
high costs for posthospital care and severe suffering of families (3, 4).
150
Systemic and selective hypothermia.
155
160
165
From animal experiments a vast body of knowledge demonstrates that a low intraischemic brain temperature or lowering brain temperature by 2-4 °C post ischemia may
protect the asphyxiated brain from neuronal damage and cell death and improve long
term neurological outcome (5-7, 47). In factually all animal experiments, hypothermia of
the brain was induced and associated with hypothermia of the rest of the body. Selective brain cooling while maintaining normal rectal temperature was demonstrated to be
possible in new-born piglets (8), but evidence of long lasting effects or superiority to
systemic hypothermia is still lacking.
In analogy, all human hypothermia studies in adults were based on systemic body
cooling. Mellegard P. demonstrated that effective selective cooling of the brain was not
possible in adult neurosurgical patients (9). Simply heat balance calculations or complex
mathematical model indicate, that selective brain cooling is only possible if one accepts
extreme temperature gradients across both, body and
brain (10).
EFFECTS
170
175
Hypothermic interventions have five domains which appear to determine the balance
between protective and adverse effects: (1) temperature range of and profile within
brain tissue, (2) time relation of occurrence of insult to inducing hypothermia, (3) duration of cooling, (4) degree of severity of the neuronal injury, and (5) developmental and
biological age of the individuum subjected to hypothermia.
Temperature range.
180
185
Though a controversial issue, most animal studies suggest, that the optimal brain temperature for neuroprotection ranges between 32 and 34 °C. In some studies mild hypothermia (34°C) was found to mitigate neuronal damage to a larger extent than moderate
(32 - 28°C) or deep hypothermia (28 - 17°C) (11,12). In other studies, mild hypothermia
was as effective in reducing biochemical and histological markers of neuronal injury and
in reducing abnormal behaviour (12 - 15).
Time relation between insult and hypothermia.
5
190
195
Hypoxic-ischemic injury resulting in encephalopathy evolves in two phases , the primary
and secundary energy failure. The primary event triggers a series of biochemical and
immunological responses which are responsible for the pathophysiology of the second
phase and for the final manifestation of cerebral damage. These biochemical and immunologic responses include release of cytotoxic neurotransmitters (13), oxygen radicals (16), inflammatory mediators and signals inducing apoptosis (17). It appears natural that an immediate or earlier intervention might be more successful than delayed
ones. In animal experiments, hypothermia induced at 1 to 5.5 hours were more effective
compared to later inductions (14,18 -20). The neuroprotective effects diminishes and
disappears if cooling is delayed beyond 6 hours (14, 20)
Duration of hypothermia.
200
205
210
215
Duration of cooling clearly relates to short and long term outcome of asphyxia (7, 14,
20), longer periods being more effective than shorter periods of hypothermia. The duration of hypothermia ranges up to 72 hours in asphyxiated animals, kept at 35°C (20). In
human trauma patients a hypothermia of about 33°C was applied for 24 hours (21). Asphyxiated human new-borns have been kept at a rectal temperature of 35.5 °C for 72
hours (22) and at a nasopharyngal temperature of 34.5° for an average of 78 hours (23)
Severity of the injury and developmental stage of the injured.
Scarce data in animal and human studies indicate that the neuroprotective impact of
hypothermia is stronger in mild than severe neuronal injury (18, 21, 24). Few and controversial studies are available which investigated the effectiveness of hypothermia on
neuroprotection in dependence of developmental age (25, 26). However, in rats of various developmental stages, brains of immature rats were found to be less resistant to
hypoxia (26). The neonatal brain undergoes drastic neuronal remodelling through
apoptosis before and after birth. Different remodelling and healing capacity in developing individuals might be responsible for the fact, that similar therapeutic procedures like
ECMO generally produce better outcome result in new-born infants than in pediatric or
adult patients (see ECMO registry).
ADVERSE EFFECTS
220
225
230
Hypothermia on one hand can be the manifestation of an underlying disease and on the
other hand the result of an accidental or actively induced heat loss. Hypothermia causes
a wide spectrum of effects on all organ systems. We suggest to classify these effects
into (i) physiological changes, which are reversible. Amongst them, low heart and
breathing rate immediately reverse to normal, when normothermia is reinstituted , (ii)
pathologic alterations, which are reversible, probably represent some health risks, but
have not shown to result in irreversible damage, either without or with treatment .
Amongst them hypoglycemia, altered coagulation states or low platelets, and (iii) alterations which result in irreversible damage despite attempts of or due to lack of effective
treatments, amongst them occurrence of intracranial tissue bleeding or untreatable cardiac arrest due to arrhythmias (although arrhythmias are not reported to occur at mild
hypothermia). Difficulties in assessing the hypothermic effects arise from possible combinations of causes, their manifestations and their consequences.
6
235
240
245
250
255
260
265
270
Accidental hypothermia and hypothermia, caused by disease or therapy, is known to
affect factually all organ systems (27, 28). Some of these effects are reversed at normothermia without causing disease or impairment. Other effects like arrhythmias, coagulation disorders or infections may have long term sequelae (29 - 34). Accidentally
cooled prematures with a rectal temperature < 34 °C at admission suffered from coagulation disorders, a high incidence of hemorrhage and mortality, whilst another group
of newly born prematures with an average rectal temperature of 31 ± 2.7 °C at admission exhibited only transient thromobcytopenia and renal failure (31,32).
In controlled clinical trials on adult trauma or cardiac arrest patients , induced mild to
moderate hypothermia for up to 24 hours resulted in some beneficial effects (21,35, 36)
without any significant, irreversible side-effects. In a study by Metz et al. on ten traumatized adults, subjected to moderate hypothermia for 24 hours, adverse effects such as
temporary decrease of cardiac index, thrombocytes and creatinine clearance, and an
elevated serum lipase activity were reported (37).
Whole body cooling had been applied to asphyxiated mature human new-borns after
delivery by Westin (38) in the sixties. Several trials treating asphyxiated term infants with
hypothermia followed without reporting details on immediate effects or complications
(39). Head cooling in 12 asphyxiated new-borns to two temperature levels (six at 36.536.0°C and six at 35.5 - 35.9°C) was reported not to result in any adverse effects which
could be specifically attributed to hypothermia (22). Incidences of adverse side effects
in asphyxiated new-borns cooled to 34.5° nasopharyngeal temperature for 3 1/2 days
were not different from those asphyxiated but kept at normal body temperature (23).
A randomized, controlled study on the effect of mild hypothermia (two arms: control vs.
head cooling method) is in process by Gluckman & Wyatt in cooperation with Olympic
Medical , Seattle, USA with the following known characteristics:
1) Hypothermia induced by external head cooling (cooling cap Olympic Medical)
2) Hypothermia maintained for three days
3) Inclusion of moderate and severe cases of asphyxia (aEEG < 5 uVolt) with an estimated chance of death or disability of 80%
4) Regulatory endpoint Trectal 34. 5± 0.5 °C
5) Study endpoint : combined rate of mortality and neurodevelopmental
impairment at 18 month of age.
7
275
280
This study will differ from the one of Gluckman & Wyatt in the following respects:
1) Systemic cooling without any efforts to achieve a temperature difference between
head and rest-of-the body by cooling the head and to add radiative heat to the
rest-of-the body.
2) Regulatory end-point is T rectal 33-34°C, a mean of 33.5 °C
3) Routine analgesia and sedation in both groups with morphine.
4) Prospectively planned assessment of treatment effect in mild to moderate vs.
severe asphyxia.
5) Option of cooling before transport
6) Trectum measured at 2-3 cm from anus, thus allowing measurements with
ubiquitous available rectal thermometers.
Study objectives
285
290
The objectives of this randomized, controlled, multicenter study are 1) to determine
whether inducing systemic hypothermia in birth asphyxiated new-born infants at term
decreases the proportion of infants who die or survive with severe neurodevelopmental
handicap when compared to new-born infants whose body temperature is maintained
within the normal range, 2) to determine whether the protective effect of hypothermia is
related to the severity of asphyxia and 3) to evaluate the safety of hypothermia.
Hypotheses
295
300
Primary: Hypothermia at 33-34°C, induced by a cooled mattress for three days in severely asphyxiated new-born infants, reduces the risk of death or severe neurodevelopmental handicap at 18 - 21 months.
Secondary (a): Hypothermia reduces neurodevelopmental retardation (measured by
Griffith GQ) at 18 - 21 months to a significant larger extent in the group with moderately
abnormal EEG compared to the group with severely abnormal EEG.
Secondary (b): Systemic hypothermia in the range 33-34°C for 72 hours is safe.
305
Study design
1.
Randomized, controlled, multicenter
neurodevelopmental outcome.
2.
The protocol and data acquisition is designed to provide a common minimal
dataset to test the primary and two secondary hypotheses by participation of
regional study groups. The common statistical analysis will be carried out by Prof.
W. Gaus, Department of Biometry and Medical Documentation, University of Ulm,
Germany.
3.
Statistical analysis will be based on intention-to-treat.
310
315
trial
with
blinded
assessment
of
8
4.
Safety and interim analyses at 1/4, 1/2 and 3/4 of patient recruitment in a fixed
sample design. A safety monitoring committee will be headed by Prof. F Pohlandt,
Dept of Paediatrics, University of Ulm, Germany. Severe adverse events, likely to
be related to hypothermia must be reported to the Department of Biometry and
Medical Documentation, University of Ulm, Germany, by fax on the same day.
5.
Regional co-ordinators are responsible for data quality. As a minimum, all entries
in patient record forms must be dated and signed, and all participating centers
must be visited by a regional monitor once per year when a sample of case record
forms must be checked against patient charts. This quality control must be
documented.
6.
Inclusion of new patients must be reported to the regional co-ordinator by fax on
the same day.
7.
Individual centres are encouraged to add on studies provided this does not
interfere with the objectives of this protocol.
8.
Centres involved in testing of new, unproven and unpublished neuroprotective
strategies for asphyxiated infants cannot participate in the study.
9.
Publication will be in the name of ‘neo-nEuro-network’ with a detailed
acknowledgement of all contributions.
320
325
330
335
10. Publication of add-on studies can be done as relevant with the mention of the participation in the neo-nEuro-network. Statistics which can be used to test the
hypotheses of this protocol must be avoided.
340
PATIENT SELECTION
6.1 Inclusion Criteria
The infant will be assessed sequentially by criteria A, B and C listed below:
A. Evidence of severe birth asphyxia in infants >36 weeks gestation admitted to the
NICU: ONE of the following
345
350
355

Apgar score of < 5 at 10 minutes after birth

Continued need for resuscitation, including endotracheal or mask ventilation, at
10 minutes after birth

Acidosis defined as either umbilical cord pH or any arterial pH within 60 minutes
of birth <7.00

Base Deficit  16 mmol/L in umbilical cord blood sample or any blood sample
within 60 minutes of birth (arterial or venous blood)
B. Evidence of encephalopathy (assessed by certified study personnel): Moderate to
severe encephalopathy consisting of altered state of consciousness: lethargy,
stupor or coma, and at least one or more hypotonia, abnormal reflexes including
oculomotor or pupillary abnormalities, an absent or weak suck or clinical seizures.
C. Evidence of moderate-to-severe neurophysiological dysfunction: At least 30 minutes
duration of amplitude integrated EEG or standard EEG recording that shows abnor-
9
mal background EEG activity or seizures (see definitions : Appendix 1). The aEEG
or EEG may be performed from one hour of age. aEEG or EEG should be read by
certified study personnel. Classification of the aEEG is according to al Naqeeb et al.
(42). The classification of the EEG is according to Lamblin et al (45). The aEEG or
EEG 30 min following IV anticonvulsant therapy, e.g. phenobarbitone should not be
used for classification.
360
Exclusion Criteria
365

Infants expected to be >5.5 hours of age at the time of randomization.

Prophylactic administration of high dose anticonvulsants (e.g. >20mg/kg phenobarbitone). After trial entry phenobarbitone or other anticonvulsant therapy may be
given as clinically indicated to treat seizures (see co-treatment below).

Major congenital abnormalities, such as diaphragmatic hernia requiring ventilation,
or congenital abnormalities suggestive of chromosomal anomaly or other syndromes that include brain dysgenesis.

Imperforate anus (since this would prevent rectal temperature recordings).

Evidence of head trauma or skull fracture causing major intracranial hemorrhage.

Infants <1,800 g birth weight.

Head circumference <(mean2SD) for gestation if birth weight and length are
>(mean2SD).

Infants ”in extremis” (those infants for whom no other additional intensive management will be offered in the judgement of the attending neonatologist). Record in detail reason for exclusion.

Overt bleeding
370
375
380
If all inclusion and no exclusion criteria are met, the infants are eligible for randomization.
385
STUDY PROCEDURES
Recording and Classification of aEEG or standard EEG (Appendix 1)
390
395
The aEEG will be recorded with a Lectromed Cerebral Function Monitor and the use of
needle electrodes inserted at an exact distance of 5 cm apart from each other at the
parietal regions. The recording speed is 1mm/min. The classification of the aEEG is
based on the publication of Niran al Naqeeb et al. (ref 42 : Pediatrics 1999; 103; 12631271) which yields two subgroups: Moderately abnormal aEEG designates mildly to
moderately asphyxiated new-borns and suppressed aEEG severely asphyxiated newborns. This classification is used for subgroup analysis.
10
400
The standard EEG is recorded according to the International 10-20 Classification. The
classification of the EEG is based on the publication of Lamblin MD et al. (ref 45: Neurophysiol Clin 1999; 29: 123 - 219)
Consent
405
Randomisation is done after informed consent from at least one parent. Consent may
be written or verbal and documented by a wittness.
Entry criteria and other parts of the minimal data set is entered in the Case Record
Form.
410
Temperature control
415
420
All infants are nursed in an open care unit (cot, radiant heater unit, bed etc). If relevant,
randomisation may be done in a local hospital and treatment started and continued
during transfer to a study center, provided temperature control and documentation is
adequate.
Body temperature is measured rectally, at least 2 cm from the anus, preferentially with a
permanent probe .
Control Group
425
Infants randomized to the control group are treated according to present standards of
postnatal care with the aim of achieving a normal body temperature i.e. T rectum of 37°C
(range: 36.5 to 37.5°C) . All handling and treatments otherwise should be identical to
the one of the hypothermia group.
Hypothermia Group
430
435
Infants randomised to the hypothermia group will be nursed naked on a cooling mattress (cooling device and matrass see: Appendix 3) which is perfused by circulating
water at a variable temperature and covered by normal linen. The infant will have a diaper around the lower half of the abdomen. The rectal temperature is targeted at 33.5 °C
(range of 33 to 34 °C). The duration of hypothermia is 72 hours.
Induction of hypothermia
440
Target temperature should be achieved within 60 min. The water temperature should
initially be set to 10°C. The body temperature should be checked every 10 min. If the
temperature drop is insufficient the cooling mattress should be wrapped around the infant or cool packs be applied.
Maintaining hypothermia
445
11
Normally a mattress temperature of 32-33°C will maintain the temperature within range.
The temperature must be recorded every hour. Be prepared to reduce matters temperature in case of seizures, to increase it at initiation of mechanical ventilation etc.
450
455
Rewarming
Rewarming is started by stopping the cooling of the mattress. Check the temperature
every hour. The infant should reach a normal rectal temperature in 6 -12 hours after
stopping cooling. If the infant does not warm up spontaneously, heat may be added
from a radiant heater. Check the temperature more frequently. If the temperature rises
more than 0.5°C per hour, the cooling mattress should be used to control the rise.
After rewarming
460
Temperature is managed according to routine care. Beware of rebound hypothermia.
Co-treatments
465
1.
All infants in the hypothermia and control group will receive morphine at 0.1 mg/kg
every 4 hours during the first three days as brain edema might and as cold does
induce discomfort, restlessness, anxiety and irritation (References: in Physiological
and Behavioral Temperature Regulation. Chapter 57. Eds. Hardy JD, Gagge AP,
Stolwijk JAJ, 1970 Charles C Thomas Publisher) and pain (Reference: Maria Fitzgerald, London, at 11 Anual ESIC Congress, Stockholm, 1998). Hypothermia increases stress hormones (48).
2.
In ventilated infants PCO2 should be maintained between 40 and 60 mmHg. In
spontaneous breathing infants hyperventilation will not be treated, but hypoventilation with PCO2 > 60 mmHg will be treated.
3.
All other treatments will be given according to clinical routines
470
475
Discontinuing hypothermia before 72 hours
1.
Parents withdraw consent.
480
2.
The attending neonatologist decides, if possible after consultation with the regional
co-ordinator (Record reason for withdrawal). Potential reasons might include for
example bleeding, thrombosis, pulmonary hypertension or arrhythmia which is
difficult to control, or continued inability to maintain rectal temperature in the
desired range.
485
3.
Need for ECMO.
If hypothermia is discontinued prior to 72 hours, rewarming will be done according to
clinical routine. The follow-up procedures will be done unless the parents withdraw their
permission for this.
490
Improvement on continuous aEEG or standard EEG recording, after trial entry, is not an
indication for discontinuing treatment.
12
Follow-up
495
7 ± 1 days postnatal : Neurological assessment by the Thompson score
(ref. 41) and brain ultrasound.
6 months: Bodyweight, length, and head circumference and gross neurological assessment (blinded assessment by certified study personnel).
500
12 months: Parental questionnaire.
505
18 month: Neurological examination and determination of Griffith General Quotient
(GQ) (blinded assessment by certified study personnel). Persistent neurological signs
consistent with a central motor deficit are classified according to five level classification
of Palisano et al (40).
Primary Outcome Measure
510
Survival at 18–21 months of postnatal age free of severe neurodevelopmental handicap.
Severe neurodevelopmental handicap is defined as one or more of
515
Neurological deficit with a functional score of 3-5 as defined by Palisano et al. (40),
i.e. sitting only with low back support or worse.
Griffith General Quotient of less than 85 (i.e. < 2 SD)
Severe bilateral cortical visual deficit (no reaction to a threat to the eye, which has a
clear anterior chamber and normal fundi)
520
Secondary outcome measures
1. Thompson Score (ref. 41) at day 7
2. Head Circumference at 6 months
525
13
Outcome measure for Subgroup Analysis
530
Subgroup analysis of infants with (1) moderately abnormal and (2) suppressed aEEG in
order to determine which of these subgroups is more responsive to hypothermia treatment. Griffith General Quotient will be used as outcome measure .
535
ADVERSE EFFECTS
Definitions
540
Potential adverse effects to hypothermia may also be consequences of asphyxia, and
thus statistical testing is essential to determine whether cooling may be a contributing
factor. Severe adverse events that in particular may be due to hypothermia will be immediately reported to the Data Safety Monitoring Committee (DSMC) . They are:
 Cardiac arrhythmia
 Severe hypotension despite full inotrope support and volume correction
 Major venous thrombosis not related to an infusion line
545
 Severe bleeding, e.g. from the lungs or in the brain
Other complications that may occur during the first 7 days of life may include:

Death

Electrocardiographic evidence of cardiac arrhythmias or myocardial ischemia or hypotension <40mm Hg

Coagulopathy (clinical bleeding with abnormal clotting studies, consistent with disseminated intravascular coagulation or hepatic coagulopathy)

Abnormal renal function (urine output <0.5 ml /kg/hour for >24 hours after birth,
maximum serum creatinine (>0.09 mM).

Hyponatremia (<130 mM), hypokalemia (<3.5 mM).

Bone marrow depression (platelet count <100,000 per mm 3)

Elevated liver enzyme levels (AST >200 IU, ALT >100 IU)

Metabolic acidosis (BE <-5) following after entry into study

Need for mechanical ventilation

Need for nitric oxide

Need for ECMO

Systemic infection (blood, CSF or urine cultures)
550
555
560
14
565

Hemoconcentration (increase of hematocrit by 20% or more) not associated with
transfusions

Hypoglycemia (<2.6 mmol/L)

Hypocalcemia (<2 mmol/L) adjusted for albumin levels, or <1.0 mmol/L on ionised
calcium measurement.
Adverse events related directly to cooling device:

Difficulties in temperature control
570
STATISTICAL ANALYSIS
575
580
Randomization
Randomization will be stratified for hospitals as well as for the severity of asphyxia
(moderate/severe). Before the start of the trial, randomization plans will be established
in the Department of Biometry and Medical Documentation of the University of Ulm,
Germany, for all hospital. The resulting group assignment for each consecutive patient
will be concealed in sealed envelopes. The envelopes are identified by
Title of study : Induced systemic hypothermia...
Name of the hospital
585
moderate / severe asphyxia
A patient number.
Each participating hospital will receive two piles of envelops, one pile for moderate asphyxia and one pile for severe asphyxia.
590
Envelopes have to be used by increasing patient number, i.e. the envelope with the
lowest patient number first.
595
600
The envelopes will contain a self adhesive label with title of study, name of the hospital,
the degree of asphyxia (moderate or severe), the patient number and finally the treatment (hypothermia or control). This label has to be placed on the case report form on
admission of a patient to the study. Then, a filled out form with the label has to be
transmitted by fax to the regional co-ordinator within 24 hours.
15
Statistical Evaluation
605
610
615
The primary null-hypothesis is: ”The proportion of surviving infants without severe neurodevelopmental handicap at the age of 18-21 months is not reduced by hypothermia”.
The test is one-sided since it is not relevant to confirm statistically whether hypothermia
increases the proportions of death or handicap.
The statistical evaluation will be performed on all admitted patients (full sample analysis,
intent to treat analysis). The result will be summarized by a 2 x 2 contingency table (outcome by group); Fisher’s exact test (level of significance: 5%) will be used to compare
the treatment groups. This test is confirmative.
The statistical evaluation of the data will include all necessary descriptive measures.
The Griffith General Quotient will be compared using a Wilcoxon test for two parallel
groups. All further secondary outcome measures will be evaluated using the appropriate
statistical procedures. These tests are one-sided, too, with a level of significance of 5%.
The levels of significance will not be adjusted for multiple testing. Hence, these tests are
only intended for exploration. At regular intervals, interim analyses will be carried out
(see below), their maximum number is 3.
620
Sample size (see APPENDIX 2)
625
630
The sample size of 2 x 75 patients has been determined under the following assumptions: 60% of the patients suffer from moderate asphyxia, 40% from severe asphyxia.
Further, 75% of the patients with moderate asphyxia and 95$ of the patients with severe
asphyxia will be dead or handicapped after 18-21 months in the control group. If 40% of
these cases can be prevented by hypothermia under moderate asphyxia and 10% under severe asphyxia, the overall proportion of dead or handicapped will be 83% in the
control group and 61% in the hypothermia group. These assumptions lead to a sample
size of 61 patients per group when testing a one-sided hypothesis at a level of 5% with
a power of 80% under the given treatment effects. It is realistic to assume that 20% of
infants will be lost to follow up. Thus 75 patients will have to be recruited in each group.
635
Data Monitoring and Interim Analysis
DATA COLLECTION & MONITORING
640
645
650
Data collection and monitoring of study centres is done by the regional co-ordinators.
Data will be passed on to the Department of Biometry and Medical Documentation, University of Ulm, for analysis. Safety and interim analyses will be done when 1/4, 1/2 and
3/4 of the patients are recruited. Severe adverse effects will be reported on the same
day to Ulm. Safety data and Interim analysis will be reviewed by the Safety and Data
Monitoring Committee (Pohlandt F, Ulm and Versmold H, Berlin and N.N).
Regional co-ordinators will meet every 6 months to maintain consistency of procedures
when documentation of site visits and sample chart reviews by regional co-ordinators
will be reviewed by the principal investigator.
16
INTERIM ANALYSIS
655
660
665
The estimated mortality in the control group is 20% to 30% (assuming a mortality in
moderate asphyxia of about 5% and in severe asphyxia of 60%, further a case mix of
60% moderate and 40% severe asphyxia).The majority of deaths after severe birth asphyxia are a consequence of brain damage, and occur within the first week of life. This
means that the study hypothesis, assuming a reduction in adverse outcome (death and
handicap) of about 30%, includes an expectation of reducing death rate from 20 to
15%; this is a difference of 5% death before 7 days. The interim analyses will be aimed
at detecting strong evidence against this. Furthermore, the adverse effects of cooling
are recorded within 7 days of life. Safety analysis will compare adverse effects in the
hypothermia and control groups.
Interim analysis will be done when 40, 75 and 115 of the patients in each group have
been recruited and 7 day data is available.
670
675
If the interim analyses show that it is highly unlikely (p < 0.0025 in the first analysis,
p < 0.005 in the following two interim analyses) that the mortality will be reduced by an
absolute difference 5% or if safety analysis shows that it is highly likely (p-values as
above) that hypothermia is associated with increased number of severe adverse effects,
premature stopping of the trial will be considered by the Data Safety Monitoring Committee.
If the trial is stopped prematurely the patients already included in the study will be followed up as scheduled by this study protocol.
680
Final Analysis
685
690
695
Final analysis will be based on intent-to-treat and carried out after follow-up is closed for
all patients on study.
The analysis will include
 Source data listing
 An elementary descriptive analysis of all variables observed
 Assessment of data quality achieved
 Description of study patients
 Assessment of drop-outs and comparability of groups
 Evaluation of efficacy including scheduled subgroups analysis
 Evaluation on adverse events, tolerability and risks of hypothermia
 Explorative analysis if further interesting results are supposed
 Biometrical assessment on validity of study results
17
700
In case there will be a serious proportion of drop-outs the most important parts of the
analysis have to be done for all admitted patients (full sample analysis) as well as for
those patients valid for efficacy.
Financial Support
705
G. Simbruner will file an application at the German Federation for Research (Deutsche
Forschungsgemeinschaft) to finance insurance, 1/2 post for a statistician, 1 post for
data monitoring doctor, and up to 10 Lectromed Ceerebral Function Monitors to increase the number of participants in Germany. Other regional co-ordinators will have to
obtain their own funds to fulfil their roles.
710
715
LITERATURE
1
Finer NN, Robertson CM, Richards RT, Pinnell LE, Peters KL. Hypoxic-ischemic
encephalopahty in term neonates: Perinatal factors and outcome. J Pediatr 1981;
98: 112-117
2
Thornberg E. Birth asphyxia: incidence, clinical course and outcome in a Swedish population. Acta Paediatr 1995; 84:927-932
3
Robertson CM, Finer NN,Grace MG. School performance of survivors of neonatal
encephalopathy associated with birth asphyxia at term. J Pediatr 1989; 114: 75360
4
Shankaran S, Woldt E, Koepke T, Bedard MP, Nadyal R. Acute neonatal morbidity and long-term central nervous system sequelae of perinatal asphyxia in term
infants. Early Hum Dev 1991; 25: 136-148
5
Busto R, Dietrich WD, Globus MYT, Valdes I, Scheinberg P, Ginsberg MD
Small differences in intra-ischemic brain temperature critically determine the extent of ischemic neuronal injury. J Cerebr Blood Flow Metab 1987; 7:
729 - 38
6
Dietrich WD. The Importance of Brain Temperature in Cerebral Injury.
J Neurotrauma 1992; 9: Suppl 2: S-475- 485
7
Thoreson M, Wyatt J. Keeping a cool head, post-hypoxic hypothermia - an old
idea revisited. Acta Paediatr 1997; 86: 1029-33
8
Gelman B, Schleien CL, Lohe A, Kuluz JW. Selective brain cooling in infant piglets after cardiac arrest and resuscitation. Crit Care Med 1996; 24: 1009-1017
9
Mellegard P. Changes in human intracerebral temperature in response to different methods of brain cooling. Neurosurgery 1992; 31: 671-677
720
725
730
735
740
745
18
10
Simbruner G.Thermodynamic models for diagnosic purposes in the new-born and
fetus; Facultas Verlag, Wien; 1983, ISBN 3-85076-133-9
11
Weinrauch V, Safar P,Tisherman S, Kuboyama K, Radovsky A. Beneficial effects
of mild hypothermia and detrimental effect of deep hypothermia after cardiac arrest in dogs. Stroke 1992; 23: 1454-1462
12
Chopp M, Knight R, Tidwell CD, Helpern JA, Brown E Welch KMA. The metabolic
effects of mild hypothermia on global cerebral ischemia and recirculation in the
cat: comparison to normothermia and hyperthermia. J Cereb Blood Flow Metabol
1989; 9: 141148
13
Busto R, Globus MYT, Dietrich D, Martinez E, Valdes I,Ginsberg MD. Effect of
mild hypothermia on ischemia-induced release of neurotransmitters and free fatty
acids in rat brain. Stroke 1989; 20: 904-910
14
Coimbra C, Wieloch T. Moderate hypothermia mitigates neuronal damage in the
rat brain when initiated several hours following transient cerebral ischemia. Acta
Neuropathol 1994; 87: 325-331
15
Clifton GL, Jiang JY, Lyeth BG, Jenkins LW, Hamm RJ, Hayes RL. Marked protection by moderate hypothermia after experimental traumatic brain injury. J
Cereb Blood Flow Metab 1991; 1:114-121
16
Armstead WM, Mirro R, Busija DW, Leffler CW. Post-ischemic generation of superoxide anion by newborn pig brain. Am J Physiol 1988; 255: H401-403
17
Edwards AD, Yue X, Cox P, Hope PL, Azzopardi D, Squier MV, Mehmet H.
Apoptosis in the brains of infants suffering intrauterine cerebral injury. Pediatr
Res 1997; 42(5) 684-689
18
Colbourne F, Corbett D. Delayed and prolonged post-ischemic hypothermia in
neuroprotective in the gerbil. Brain Research 1994; 654: 265-272
19
Gunn AJ, Gunn TR, Gunning MI, Williams CE, Gluckman PD. Neuroprotection
with prolonged head cooling started before post-ischemic seizures in fetal
sheep.Pediatrics 1998; 102 (5): 1098-1106
750
755
760
765
770
775
780
19
785
20
Sirimane ES, Blumberg RM, Bossano E, Gunning M, Edwards AD, Gluckman
PD,Williams CE. The effect of prolonged modification of cerebral temperature on
outcome after hypoxic-ischemic brain injury in the infant rat. Pediatr Res 1996; 9:
591-597
790
21
Marion-DW; Penrod-LE; Kelsey-SF; Obrist-WD; Kochanek-PM; Palmer-AM; Wisniewski-SR; DeKosky-ST. Treatment of traumatic brain injury with moderate hypothermia. N Engl J Med 1997; 336: 540-546
22
Gunn AJ, Gluckman PD, Gunn TR. Selective head cooling in newborn infants
following perinatal asphyxia; a safety study. Pediatrics 1998; 102 : 885 - 892
23
Simbruner G, Haberl C, Harrison V, Linley L. Induced brain hypothermia in asphyxiated human newborn infants: a retrospective chart analysis of physiological
and adverse effects . Int Care Med 1999; 25:1111-1117
24
Chopp M, Chen H, Dereski MO, Garcia JH. Mild hypothermic intervention after
graded ischemic stress in rats. Stroke 1991; 22: 37-43
25
Berger R, Jensen A, Hossmann KA, Paschen W. Effect of mild hypothermia during and after transient in vitro ischemia on metabolic disturbances in hippocampal
slices at different stages of development. Dev Brain Res 1998; 105: 67-77
26
Yager JY, Shuaib A, Thornhill J.The effect of age on susceptibility to brain damage in a model of global hemispheric hypoxia-ischmia. Dev Brain Res 1996; 93:
143-154
27
Cornell HM. Accidental hypothermia. J Pediatr 1992; 120: 671-79. 28
28
Ilievich UM, Spiss CK. Hypothermic therapy for the injured brain. Current Opinions in Anesthesiology 1994; 7:394-400
29
Okada M. The cardiac rhythm in accidental hypothermia. J Electrocardiol 1984;
17: 123-128
30
Mann TP, Elliot RIK. Neonatal cold injury due to accidental exposure to cold.
Lancet 1957; 1, 229
31
Chadd Ma, Gray OP. Hypothermia and coagulation defects in the newborn. Arch
Dis Child 1972: 41: 819-821
32
Kaplan M, Eidelman AI. Improved prognosis in severely hypothermic newborn
infants treated by rapid rewarming. J Pediatr 1984; 105: 470-74
33
Staab BD, Sorensen VJ, Fath JJ, Raman SBK, Horst HM, Obeid FN. Coagulation
defects resulting from ambient temperature-induced hypothermia. J Trauma
1994; 36: 634-8
795
800
805
810
815
820
825
830
20
34
El-Radhi AS, Jawad MH, Ibrahim M, Jamil II. Infection in neonatal hypothermia.
Arch Dis Child 1983; 58 (2): 143-145
35
Shiozaki T, Sugimoto H, Tenada M, Yoshida H, Iwai A, Yoshioka T, Sugimoto T.
Effect of mild hypothermia on uncontrollable intracranial hypertension after severe head injury. J Neurosurger 1993; 79: 363-368
36
Bernard SA, Jones BM,Horne MK. Clincal trial of induced hypothermia in comatose survivers of out-of-hospital cardiac arrest. Ann Emerg Med 1997; 30: 146-53
37
Metz C, Holzschuh M, Bein T, Woertgen C, Frey A, Frey I, Taeger K, Brawanski
A. Moderate hypothermia in patients with severe head injury: cerebral and extracerebral effects. J Neurosurgery 1996; 85: 533-541
38
Westin B, Nyberg R, Miller JA, Wedenberg E. Hypothermia and transfusion with
oxygenated blood in the treatment of asphyxia neonatorum. Acta paediatr Scand
1962; 51; Suppl 139: 1-80
39
Miller JA, Miller FS, Westin B. Hypothermia in the treatment of asphyxia neonatorum. Biol Neonate 1964; 6: 148-163
40
Palisano R, Rosenbaum P, Walter S, Russell D, Wood E, Galuppi B.
Development and reliability of a system to classify gross motor function in children with cerebral palsy. Dev Med Child Neurology 1997; 39: 214-223
41
Thompson CM, Puterman AS, Linley LL, Hann FM, van der Elst CW, Molteno
CD, Malan AF. The value of a scoring system for hypoxic ischaemic encephalopathy in predicting neurodevelopmental outcome. Acta Paediatr 1997; 86: 75761
42
al Naqeeb N, Edwards AD, Cowan FM, Azzopardi D. Assessment of Neonatal
Encephalopathy by Amplitude-intergrated Electroencephalography. Pediatrics
1999; 103; 1263-1271
835
840
845
850
855
860
865
43
870
Hellström-Westas L, Rosén I, Svenningsen NW (1995) Predictive value of
early continuous amplitude integrated EEG recordings on outcome after severe
birth asphyxia in full term infants. Arch Dis Child 72: F34-F38
44
875
Toet MC, Eken P, Groenendaal F, de Vries LS Comparison of amplitude
integrated EEG in birth asphyxiated term neonates between 3 and 6 hours
after birth (Abstr 1902, Neurology; Ped Res 1998; 43, Part 2 of 2)
21
45
Lamblin MD, Andre M, Challamel MJ, Curzi-Dascalova L, dÁllest AM, De Giovanni E , Moussalli-Salefranque F, Navelet Y, Plouin P, Radvanyi-Bouvet MF,
Samson-Dollfus D, Vecchierini-Blineau MF. Electroencephalographie du nouveau-ne premature at a term. Aspects maturativs et glossaire. Neurophysiol Clin
1999; 29: 123 - 219
46
Thoresen M and Wyatt J. Review article . Acta Paediatr 1997; 86: 1029-33
Keeping a cool head, post-hypoxic hypothrmia-an old idea revistied
(References 29- 34)
47
Thoresen M, Cooling the newborn aftrer asphyxia - physiological and
experimental background and its clinical use. Semin Neonatol 2000; 5:61-73
48
Thoresen M, Satas S, Loberg EM, Lindgren C, Acolet D, Steen PA, Haug E,
Whitelaw A. Pediatr Res 1999; 45: 46 A
880
885
890
895
22
APPENDIX 1
900
Procedures and definitions for neurological assessment, aEEG and EEG
assessment
Assessment of Neurological Signs
905
Neurological signs are observed and scored according to Thompson et al (41).The
score consists of a clinical assessment of nine signs. Each sign is scored from 0 to 3
and the score for each day is totalled. The higher the score the more severely affected
the infant. The maximum possible score on any day is 22. The score is equally applicable to ventilated infants . It cannot be applied to paralyzed infants.
910
Score
Sign
915
920
Tone
LOC
Fits
Posture
Moro
Grasp
Suck
Respir
Fontanell
0
normal
normal
none
normal
normal
normal
normal
normal
normal
1
hyper
hyperalert, stare
< 3 per day
fisting, cylcing
partial
poor
poor
hyperventilation
full, not tense
2
3
hypo
flaccid
lethargic
comatouse
> 2 per day
strong distal flexion decerebrate
absent
absent
absent ± bites
brief apnea
IPPV (apnea)
tense
925
Recording of aEEG and Standard EEG
930
The aEEG will be recorded with a Lectromed Cerebral Function Monitor and the use of
needle electrodes inserted at an exact distance of 5 cm apart from each other at the
temples. Different distances result in different voltage (Personal communication: Hellström-Westas L, Blennow M). The recording speed is 1mm/min. At least one half hour
recording is required, latest between 5.0 and 5.5 hours of age. A 30 min decrease of
lower voltage margine below 5uV must not be associated with sleep cylces, manipulations or drug administration.
935
The Standard EEG is recorded according to the International 10-20 classification.
Classification of aEEG for Inclusion Criteria
940
The classification of the aEEG is based on the publication of Niran al Naqeeb et al.
(ref 42 : Pediatrics 1999; 103; 1263-1271). It yields three subgroups: normal aEEG,
moderately abnormal aEEG and suppressed aEEG. Moderately abnormal aEEG designates mildly to moderately asphyxiated new-born and suppressed aEEE severely asphyxiated new-borns. This classification is used for subgroup analysis. Patients with the
23
945
unlikely aEEG combination of upper margin < 10 uV and lower margin >5uV will remain
unclassified and excluded from the study.
Classification of standard EEG for Inclusion criteria
950
The classification of the standard EEG is based on the publication of Lamblin MD et al.
(ref 45: Neurophysiol Clin 1999; 29: 123 - 219)
955
Definition of normal EEG:
Continuous , no intervals > 3 sec and no amplitudes < 10 uV
Definition of abnormal EEG:
Continous low voltage < 25 uV or discontinuous (burst supression)
see exact definition 4.1 , 4.2 and 4.4 , 4.5 in article of Lamblin et al.
960
Sampling rate: Every 5 min a time sample of 20 sec long tracing
965
24
APPENDIX 2
970
Scientific basis for inclusion criteria, classification into subgroups and
sample size calculations.
975
980
This study includes all asphyxiated new-borns whose aEEG or standard EEG is not
normal at any time within the first six hours of age. Infants with a normal aEEG or Standard EEG, not included into the study, may later turn out to have an neurodevelopmental impairment. The false negative rate (normal EEG, but abnormal outcome) might
range from 4% to 15% (42 - 44). The study population will contain mild to moderate encephalopathy and severe encephalopathy. These two subgroups will be classified before the intervention and within the first 6 hours of age according to their aEEG or standard EEG (see APPENDIX 1) .
Event rate
985
990
The event rate is defined as death or neurodevelopmental impairment of survivors. Depending on the severity, asphyxia causes a certain rate of neurodevelopmental impairments. The table shows the event rates of ”death and neurodevelopmental impairment
”in dependence of the initial severity classified according to aEEG into the two subgroups. Estimated from data from Hellström-Westas et al, Toet et al and AlNaqeeb et
al. (42 - 44).
Correlation of ampliutde-integrated EEG to neurological outcome
995
Severity
Author
Normal
al Naqueeb 9
Hellström
26
Toet
26
1005
Moderate
abnormal
aEEG
al Naqeeb
Hellström
Toet
1010
Suppressed
aEEG
al Naqeeb
Hellström
Toet
1000
Nr
Event rate (%)
Disabilty and Death
Event rate (%)
No Disability
0
1
4
(0%)
(4%)
(15%)
9
25
22
(100%)
(96%)
(85%)
17
14
13
13
11
10
(75%)
(77%)
(77%)
4
3
3
(25%)
(23%)
(23%)
12
5
5
12
5
5
(100%)
(100%)
(100%)
0
0
0
(0 %)
(0%)
(0%)
25
Summarized Results of aEEG Studies
1015
No disability
Normal aEEG
Abnormal aEEG
Disability
and death
5
56
61
56
10
66
1020
Nr.
61
66
239
Sensitivity 56/61 = 92 % ; Specificity 56/66 = 85%
1025
Correlation of standard EEG to neurological outcome
(analyzed according to criteria of Lamblin MD et al., to be published d ´Allest AM et al.)
No disability
1030
Normal EEG
Mod abn EEG
128
Disability
and Death
Nr.
(96%)
5
(4%)
133 (55.6 %)
17 (54%)
14
(46%)
31 (13.0 %)
2 (3%)
73
(97%)
75 (31.4 %)
1035
Severe abn EEG
147
30
239
1040
Summarized Results of Standard EEG
No disability
Disability
and death
Nr.
128
19
5
87
133
106
147
92
239
1045
Normal EEG
Abnormal EEG
1050
1055
Sensitivity 87/92 = 95 % ; Specificity 128/147 = 87 %
These data on aEEG and standard EEG on neurodevelopmental outcome demonstrate:
(i) that aEEG and standard EEG have a similarly high predicitve power (92% vs 95%
sensitivity and 85% vs 87% specificity). Consequently both methods are valid for the
inclusion of asphyxiated infants.
(ii) that the ratio of moderate to severe aEEG findings is 66 % and 33% respectively in
the compiled aEEG studies (ref 42-44) and the ratio of moderate to severe in the standard EEG Data (see above) is 30% vs 70%.
26
1060
Consequently an overall ratio of 60% moderate and 40% severe asphyxia was assumed
for sample size calculation and
iii) because of the lack of congruence of subgroups defined by aEEG and standard
EEG, subgroup analysis will be done only on patients with aEEG inclusion criteria.
1065
Treatment effect
1070
1075
1080
1085
In six new-born animal studies the neuroprotection (expressed as reduction in % cell
damage or abnormal neurobehavior) of mild to moderate hypothermia starting within
30 min after the ischemic-hypoxic insult varied between 25 to 80% (the neuroprotective
effect was > 50%, when those studies where hypothermia was induced only for <3 hrs,
were excluded (46)). No data for the treatment effect of asphyxiated human new-borns
are available. The study population will contain infants with mild to moderate encephalopathy. In animal experiments hypothermia has been shown to be more effective in
mild to moderate asphyxia than in severe to fatal asphyxia (Chopp M et al. Mild hypothermic intervention after graded ischemic stress in rats. Stroke 1991; 22: 37-43).
Gluckman et al in the Olympic Medical Protocol assumed a 30 % reduction of neurodevelopmental impairment and death (an event rate of 70% in the control and 49% in the
intervention group) in a group of mixed (moderately and severely) asphyxiated newborns. We thus assumed a 40% reduction (less than the 50% in animal experiments,
but more than the 30% for the mixed group) for the mildly to moderately and 10% (less
than the mixed group) for the severely asphyxiated group.
27
APPENDIX 3
Specifications for cooling mattress and aEEG device
1090
Cerebral Function Monitor (CFM)
The CFM to be used for the study is the one from Lectromed or proven equivalent.
1095
1100
1105
Specification:
LECTROMED Cerebral Function Monitor
Lectromed MT2-5330 CFM System
Representative in Germany:
FBI Fred Berninger Importe OHG
Bergstraße 12,
D-82024 Taufkirchen, Germany
Tel.: + 49 89 61 453 453 or +49 161 2832755
Fax.: + 49 89 61 453 453
e-mail > BERNIMPORT@AOL.com
Cooling Device
1110
The cooling device to be used for the study is the one of TEC.COM GMBH. It consists
of an apparatus which provides a perfusion flow of a temperature regulated fluid and a
mattress. A simpler version Tecovit 200 for NICU use and transport, with battery 12 V
powering, is available.
1115
Specification:
Cooling device Tecotherm TS med 200 (about 3200 Euro) , size 420 x 190 x 350 mm,
ca 10 kg; Temperatue range : 5 - 42°C ; hand controlled
OR
1120
1125
1130
Tecovit 200 (about 1750 Euro)
plus CSZ Cooling matrass, rectangular, cleanable surface, ca.80 x 60 cm (about
90 Euro)
TEC.COM GMBH Prof Dr K Berndt
Product Manager
Böllberger Weg 170
D - 06128 Halle/Saale, Germany
Tel.: + 49 (0) 345 – 120 52 04
Fax.: + 49 (0) 345 – 120 52 11
e-mail >berndt-halle@t-online.de<
OR >SCHOEPKE:teccom@t-online.de
28
APPENDIX 4
Monitoring Schedule
1135
1140
1145
1150
Time
Data Sets
adm before 3
12
24
48
72
CerFunction aEEG
x----- continous------x
x
x
x cont x
Rect Temp ( Thermom )
Cooling Fluid Temp x
Environm Temp
x
x -----------------hourly----------------------x -----------------hourly----------------------- x
x
x
x
x
x
x
x
x
Blood Pressure
Heart rate
Breathing rate
SpO2
PtcCO2
Respir Variables
Urine output (3hrs)
Blood Samples
blood gases
glucose
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Clinical Examination
Neurol Examination x
x
x
x
x -----------------hourly----------------------x -----------------hourly----------------------x -----------------hourly----------------------x -----------------hourly----------------------x -----------------hourly----------------------x
x
x
x
x
x
x x
x
x
x
x
x
80 hrs
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
1155
Ultasound Imaging
x
Organ Failure
Blood samples
electrolytes
hemoglobin
coagulation
infection screen
kidney function
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
amylse
endocrine
lactate
x
x
x
1160
1165
1170
1175
Liquor
lumbal
Blood S-100, NSE
Time
x
x
x
x - between - x
x - between - x
adm before 3
12
24
48
72
80 hrs
29
Appendix 5
1180
Case Report Forms