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Study protocol:

Induced systemic hypothermia in asphyxiated new-born infants: a randomized, controlled, multicenter study

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

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

Status:

3 May 2000

Study protocol :

Induced systemic hypothermia in asphyxiated new-born infants:

a randomized, controlled, multicenter study.

________________________________________________________________

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.

Prinicipal Investigator:

Simbruner G, Division Neonatology, Ludwig-Maximilians University, Munich

Fax : + 49 89 5160 - 4419 ; e-mail > simbruner@kk-i.med.uni-muenchen.de

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

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 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

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 side-effects.

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 .

Background

Ethical considerations.

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 investigators 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.

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).

Systemic and selective hypothermia.

From animal experiments a vast body of knowledge demonstrates that a low intra-ischemic 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

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.

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.

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.

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

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.

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 36.5-36.0°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.

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

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

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.

Study design

1. Randomized, controlled, multicenter trial with blinded assessment of 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.

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.

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.

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

υ Apgar score of < 5 at 10 minutes after birth

υ Continued need for resuscitation, including endotracheal or mask ventilation, at 10 minutes after birth

υ Acidosis defined as either umbilical cord pH or any arterial pH within 60 minutes of birth 5.5 hours of age at the time of randomization.

υ 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).

υ Major congenital abnormalities, such as diaphragmatic hernia requiring ventilation, or congenital abnormalities suggestive of chromosomal anomaly or other syndromes that include brain dysgenesis.

υ Imperforate anus (since this would prevent rectal temperature recordings).

υ Evidence of head trauma or skull fracture causing major intracranial hemorrhage.

υ Infants 60 mmHg will be treated.

3. All other treatments will be given according to clinical routines

Discontinuing hypothermia before 72 hours

1. Parents withdraw consent.

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.

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.

Improvement on continuous aEEG or standard EEG recording, after trial entry, is not an indication for discontinuing treatment.

Follow-up

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).

12 months: Parental questionnaire.

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

Survival at 18–21 months of postnatal age free of severe neurodevelopmental handicap.

Severe neurodevelopmental handicap is defined as one or more of

← 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)

Secondary outcome measures

1. Thompson Score (ref. 41) at day 7

2. Head Circumference at 6 months

Outcome measure for Subgroup Analysis

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 .

ADVERSE EFFECTS

Definitions

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

← 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:

υ Death

υ Electrocardiographic evidence of cardiac arrhythmias or myocardial ischemia or hypotension 0.09 mM).

υ Hyponatremia ( ................
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