Evaluation of Lactate Dehydrogenase as Decision Support for Admissions to Neonatal Ward
Condition: Neonatal; Asphyxia
MeSH terms: Asphyxia
Study type: Interventional

Summary: 
      The immediate newborn period is the period of highest morbidity in life. Early signs of
      serious disease are often vague and difficult to interpret for the non- specialist. Screening
      lists of clinical signs are useful but have unsatisfactory specificity or sensitivity, cover
      only one or two diseases, and are complicated to handle in low resource settings.

      In critically ill newborns, organ failure to one or multiple organ systems is frequently seen
      due to inadequate circulation to the tissues. Critical disease will cause hypoxia ischemia of
      the cells in the affected organs followed by energy deficiency. Independently of the
      condition causing the energy deficiency this will start a series of events, which initially
      cause a leaking cell membrane leading to that intracellular components, i.e. the enzyme
      Lactate dehydrogenase (LDH), will leak out into the blood. Previous research in newborns
      suggests that LDH is a clinically interesting early predictor of serious illness and may thus
      serve as an important complement to the clinical examination. If the LDH level is elevated
      the health care personnel will realize that something is wrong and call for appropriate
      measures.

      Today LDH analysis is performed at the Dept. of Clinical Chemistry with an inexpensive and
      accurate method. However, this method needs relatively large blood volumes and the delay
      between blood sampling and results is rather long, often several hours. In addition LDH is
      sensitive to hemolysis, which is quite common in blood sampling in newborns. When this is
      detected at the laboratory a new sample will be needed, thus delaying the result even more.
      Also, smaller health care facilities rarely have the laboratory equipment needed for the
      analysis of LDH.

      The Swedish company Calmark Sweden AB is now launching a point-of-care technology for LDH
      analysis called "Hilda Neo". LDH is analyzed on an easy-to-use consumable test card together
      with an "App" on an ordinary smartphone (in the planned study, iPhone 4S). The result is
      presented within minutes and presence of hemolysis will be simultaneously detected on the
      device.

      The investigators speculate that the use of such a LDH test could serve as a diagnostic help
      for health-care staff in Vietnam in making the decision when to send a potentially sick
      newborn to a higher level neonatal unit (in this case the NICU at NPH, Hanoi)
    

Detailed description: 
      Patients and Methods At admission to NPH, newborn (GA >32 w, ≤36h old) infants referred to
      NPH with suspect or probable clinical signs of illness for which the physician on call
      considers that a blood sample is needed will be included in the study when a doctor taking
      part in the study is present at the ward. When a blood test is indicated, around 2 ml of
      blood is routinely drawn including an extra 0.1 ml blood for analysis of LDH using the Hilda
      Neo card.

      When an infant fulfils the inclusion criteria the physician on duty will open a downloaded
      "App" on the provided smartphone and take a photo of the first page of the study protocol
      including the patients study number time of birth, and the result of the clinical
      investigation on a simple clinical score protocol. Then the physician presses a "randomise
      button" on the smartphone to randomise to using the Hilda Neo card or to routine care. If
      randomised to the Hilda Neo card use the "app" gives instructions how to use the card and
      guides through the different steps of the test. The result of the LDH test will be presented
      to the physician immediately at the point-of-care and can be used in the clinical decisions.

      To prepare for a following study of the usefulness of LDH when deciding if a baby is ready
      for transfer from the NICU to ordinary care all included infants will have an LDH test at the
      routine clinical laboratory daily when other blood samples are drawn. The investigators
      believe that two LDH tests at 6 - 24 hour intervals are needed for that question. The reason
      for using two tests with an interval is that a high single LDH value can be expected in a
      large number of the infants because of the preceding disease while a decreasing value might
      be a better predictor of an improving status.

      An evaluation protocol is filled in by the neonatologist in the ward 80-96h after admission
      or, if earlier, at discharge or death. The classification of the protocols into "need for"
      and "no need for intensive care resources" will be done independently by two senior
      neonatologists, both blinded to the LDH results from the Hilda card and the routine clinical
      laboratory.

      The outcome that will be reported is the number of patients admitted to correct level of
      care, NICU or level 2 unit, in the two groups the admitting doctor has or has not access to
      plasma LDH respectively.

      The definitions of correct or not correct admission level were:

        1. Admitted to NICU care: correct decision=The patient did fulfil the criteria for referral
           to NICU during the first 80 and 96h after admission.

        2. Admitted to NICU care: not correct decision=The patient did not fulfil the criteria for
           referral to NICU during the first 80 to 96h after admission.

        3. Admitted to level 2 unit: correct decision=The patient did not fulfil the criteria for
           referral to NICU during the first 80 to 96h after admission.

        4. Admitted to level 2 unit: not correct decision= The patient did fulfil the criteria for
           referral to NICU between 80 and 96h after admission The classification of the protocols
           into "fulfil or not fulfil the criteria for intensive care resources" was done
           independently by two senior neonatologists, both blinded to the LDH results from the
           Hilda card and the routine clinical laboratory.

      The criteria for "fulfil the criteria for intensive care resources" were that shock-,
      ventilator-, CPAP- treatment, blood exchange, parenteral nutrition or other procedures
      demanding NICU capacity in the actual setting were performed during the first 80 - 96 hours
      after admission.

      For calculation of the number of patients needed for the study outcome "right decision" in
      relation to "wrong decision" will be used, see below under Power.

      The results will be recorded on the paper protocol forms, which are kept with the clinical
      record of the patient. The results will also be kept as a photo using the Smart phone App
      where it can be read only until the picture has been sent to the register. When the picture
      comes to the register it is identified only by its study number. Name and identity together
      with the study number is taken from the patient record to a separate register, which is
      securely kept by one authorized person in order for future supplementary information. The
      data recorded for the study are those normally recorded for a NICU patient and the doctors
      evaluation of the Hilda card.

      The de-identified protocols will be saved, processed and analysed with the statistical
      program SPSS. Only persons involved in the study will have access to the data registered.

      Based on going (Itzel et.al) and previously conducted research a LDH activity exceeding
      600U/L will be considered as increased.

      Power calculation In the investigators earlier study about 75% of the babies admitted to the
      NICU did not need intensive care procedures during the first week. To detect a reduction from
      75 to 50% according to outcome above would need 58 patients in the test and the control group
      respectively. The control group here is the group that is not admitted to the NICU ward but
      to the ordinary care ward.

      If there are technical or other problems with the Hilda Neo test that might influence the
      primary outcome the study will include 58 babies after the problem has been solved.

      The background factors and the criteria for need of intensive care that will be noted are
      presented on the protocols, (n= 120+20 patients)
    

Intervention name(s): The Neo Hilda; Traditional evaluation; iPhone 4S
Intervention type(s): Device; Procedure; Device
Intervention description(s): This is a procedure that measures Lactate dehydrogenase in a fast and reliable way from only 10 microliter of blood. Using a small point of care card and a Smartphone for analysis.
Point of care method; Traditional way of evaluation
Other intervention name(s): Neo Hilda, Calmark Sweden AB
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Diagnostic
Keywords: Classification; HIE; Infections; Lactate dehydrogenase; Intensive Care