A randomized blinded trial to assess whether near infrared spectroscopy measures of cerebral saturation in infants <28 weeks gestation enables clinicians to maintain a defined cerebral oxygen target range

MANUSCRIPT CITATION:

Hyttel-Sorensen S, Pellicer A, Alderliesten T, et al. Cerebral near infrared spectroscopy oximetry in extremely preterm infants: phase II randomised clinical trial. BMJ 2015;350:g7635. PMID 25569128.

REVIEWED BY:

Haresh Kirpalani BM, MSc;
Professor of Pediatrics, Children’s Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine

TYPE OF INVESTIGATION:

Monitoring

QUESTION:

In infants <28 weeks gestation, does provision of near infrared spectroscopy (NIRS) readings in real-time and a treatment algorithm to stabilize it, versus not having NIRS-data, result in longer time spent at a defined cerebral oxygen saturation target between 55-85% (i.e. free of burden of hypoxia and hyperoxia), over hours 3 to 72 of life?

METHODS:

  • Design: Randomized
  • Allocation: Blinded-web-randomization, stratified for <26 weeks or >26 weeks; not by site. Twins were randomized to same group, unless there were not enough machines available, in which case only the second twin was randomized.
  • Blinding: Blinded at several levels; Allocation (see above); results of NIROSCOPY were blinded in one group to physician and caregivers; to data extraction team (the primary outcome computed – blinded to allocation group – from the raw regional tissue hemoglobin oxygen (rStO2) data and extrapolated to 72 hours. There was no manual removal of artifacts in the rStO2 data, and finally this raw data was blinded by group to analysts. Head Ultrasound (US) for secondary outcomes were read centrally and blinded.
  • Follow-up period: Until hospital discharge.
  • Setting: European centers.
  • Patients: Infants born gestational age <27 weeks and six days, given full life support and able to start NIRS within three hours after birth; and parental consent. BW median NIRS 806 g control 880 g; GA median NIRS 26.6 weeks control 26.8 weeks. Groups were similar for potential confounders of later cerebral stability of saturation: prenatal steroids, chorioamnionitis, and number Apgar score <5 at 5 minutes, or mean umbilical arterial pH.
  • Intervention: Randomization to either experimental group (NIRS with visible unblinded reading of rStO2) or control group (NIRS with blinded rStO2 – i.e. physicians could not see the saturation data. This was achieved by either locking the devices in a box or by using a device specific research mode rStO2 blinding.). Eligible devices: INVOS 5100C with adult SomaSensor,NIRO 300, NIRO 200NX with small probe holder (Hamamatsu Phototonics, Hamamatsu City, Japan), or the NONIN EQUANOX 7600 with adult sensor, model 8004CA (Nonin Medical, Plymouth, MN). Data on rStO2 was recorded every five or six seconds. For the unblinded NIRS group, an rStO2 alarm warned when a burden of deviating rStO2 had accumulated during the past 10 minutes. This allowed clinicians to utilize a dedicated treatment guideline to normalize an out of range rStO2. These interventions were based on respiratory and circulatory instructions and aimed to optimize other variables (eg BP, CO2, PaO2). This was developed by the SafeBoosC group group1 and using methods of grading of the US Preventive Services Task Force 2001 system.2
  • Outcomes:
    • Primary outcome: Time spent outside cerebral oxygen target range of 55-85% multiplied by the mean absolute deviation; termed “burden of hyperoxia and hypoxia” (units as % hours).
    • Secondary outcomes: Secondary outcomes were all cause mortality at term equivalent age and degree of IVH on cerebral ultrasonography.
  • Analysis and Sample Size: Unpublished data on 23 extremely preterm infants showed a mean burden of 76.0 (SD 83.2) %hours. This was log transformed to achieve normal distribution with a mean of 1.64 (SD 0.50). Sample size targeted detection of at least 50% reduction in burden of hypoxia and hyperoxia (mean difference of 0.3 after log transformation), α 0.05 and power of 95%, adjusted for twin recruitment and intraclass correlation coefficient of 0.33. Target for enrollment: 166 infants, approximately 83 per intervention group.
  • Patient follow-up: To term corrected age, all 166 included in intention-to-treat analysis.

MAIN RESULTS:

370 infants were screened of whom 166 were randomized, NIRS 86 control 80. Monitoring time with an rStO2 signal overall was 67.7 hours (median, range 0.9-71.4 hours). The main results are summarized below.

Primary Analysis
Outcome Unblinded NIRS(n=86) Control or blinded NIRS (n=80) Relative difference (95%CI) P value
Burden of hypoxia-hyperoxia Median (IQ range) in % hours 36.1 (9.2-79.5) 81.3 (38.5-181.3) -58 (-35 to -74) <0.001
Secondary Analysis of Outcome
Unblinded NIRS Blinded NIRS Adjusted Relative Risk (95%CI) P value
Mortality at term 12/86 (14%) 20/80 25% 0.5(0.29 to 1.00) 0.10
IVH None 26% 34%
IVH Mild-moderate 61% 43%
IVH severe 13% 23% 0.11

The intervention effect varied by site with heterogeneity between sites (P<0.001). This finding was seemingly related to 1 site which when removed from analysis rendered heterogeneity insignificant (P=0.62). In fact this centre had the largest reduction in hyperoxia-hypoxia burden with NIRS. A post hoc sensitivity-analysis assessed what would have been seen if this well-experienced centre had operated like the other centers. In this analysis, at this one site, the burden of combined hypoxia-hyperoxia was very clearly reduced by 31%, reducing the p value (P=0.0497).

CONCLUSION:

The authors conclude that periods of combined cerebral hypoxia and hyperoxia were significantly reduced by monitoring, when treated in the unblinded NIRS group (i.e. where clinicians could see and thus presumably respond to the oxygen saturation data). However to assess the long term benefit and harm of the combination of NIRS and treatment guideline, larger randomized clinical trials are needed.

COMMENTARY:

This paper3 evaluates a “new” technology that has aroused much interest since the first descriptions in newborns in 1988.4 Newborn data has since been provided using similar technology for many purposes, including: assessments of brain response to transfusion,5 gut monitoring for signs that may presage NEC,6 predicting outcome in cardiac disease,7 for cerebral monitoring during cardiac anesthesia,8 and for predicting adverse IVH outcomes in preterms.9 However no definitive evidence for clinically relevant effects of monitoring this have been yet provided.

Therefore the current trialists are to be commended for taking a very careful methodological approach, here using an RCT design, to evaluate a monitoring device.3 Moreover, this reviewer worries that this monitoring device appears to be exploding into use with an inadequate understanding or data of its benefits and limitations. No severe adverse reactions were reported. However associated with the device, 16 infants had skin marks from the NIRS sensors. Skin damages in extremely preterm infants are common and can precede severe adverse reactions such as nosocomial infection.

The current report finds no significant difference in clinical outcomes, although the authors claim “trends” are seen.3 It is notable that the periods of unacceptable targeted ranges of cerebral saturations were especially reduced in one center (see the sensitivity analysis). This suggests that training is critical and that any effect of clinical relevance must have a ‘learning effect’ – that any future trial must reckon with. Moreover, whether or not the current targets of cerebral oxygen saturation chosen in this study, are optimal may need further clarification. The trialists restricted interventions to a limited range of instruments. This was wise as studies have shown considerable variation between measures obtained by differing devices.10 So much further validation and clinical demonstration must be provided before this becomes a standard of care. Finally, the details of the interventions proposed in the unblinded arms will likely require considerable further discussion.

As the trialists themselves point out, further randomized trials are needed. To emphasize this further, the on-going saga of the oxygen saturation trial differences, and the interpretation of their varying results11 – strongly argues for a cautious approach in oxygen saturation technology. Since NIRS was first introduced in 1988, it is long over-due for careful assessments.

REFERENCES

  1. Pellicer A, Greisen G, Benders M, et al. The SafeBoosC phase II randomised clinical trial: a treatment guideline for targeted near-infrared-derived cerebral tissue oxygenation versus standard treatment in extremely preterm infants. Neonatology 2013;104:171-8.
  2. Harris RP, Helfand M, Woolf SH, et al. Current methods of the US Preventive Services Task Force: a review of the process. Am J Prev Med 2001;20:21-35.
  3. Hyttel-Sorensen S, Pellicer A, Alderliesten T, et al. Cerebral near infrared spectroscopy oximetry in extremely preterm infants: phase II randomised clinical trial. BMJ 2015;350:g7635.
  4. Edwards AD, Wyatt JS, Richardson C, Delpy DT, Cope M, Reynolds EO. Cotside measurement of cerebral blood flow in ill newborn infants by near infrared spectroscopy. Lancet 1988;2:770-1.
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  9. Balegar KK, Stark MJ, Briggs N, Andersen CC. Early cerebral oxygen extraction and the risk of death or sonographic brain injury in very preterm infants. J Pediatr 2014;164:475-80 e1.
  10. Dix LM, van Bel F, Baerts W, Lemmers PM. Comparing near-infrared spectroscopy devices and their sensors for monitoring regional cerebral oxygen saturation in the neonate. Pediatr Res 2013;74:557-63.Manja V, Lakshminrusimha S, Cook DJ. Oxygen Saturation Target Range for Extremely Preterm Infants: A Systematic Review and Meta-analysis. JAMA Pediatr 2015.
  11. Manja V, Lakshminrusimha S, Cook DJ. Oxygen Saturation Target Range for Extremely Preterm Infants: A Systematic Review and Meta-analysis. JAMA Pediatr 2015.