Relationships between HRV metrics and temperature remained consistent when considering only esophageal temperatures, except for αS which remained negatively associated with temperature although this relationship did not reach statistical significance in the reduced models (Table 2). Although the interaction between encephalopathy grade and temperature was not significant, we proceeded with analyses after stratifying by encephalopathy grade to assess the impact of this important confounder. Infants with moderate encephalopathy showed similar relationships between HRV and temperature as the overall cohort. Although only eight patients had severe encephalopathy, significant associations between median RRi (estimate, –0.045; p = 0.009) and RMSS (estimate, –0.148; p = 0.007) were observed in these patients.
This is the first clinical study to evaluate the relationship between HRV and temperature in newborns undergoing TH. Across the range of temperatures observed during the rewarming period, we demonstrate a significant relationship between several HRV metrics and temperature. Specifically, we observed an overall reduction in HRV as temperature increased toward normothermia. This has important implications as the use of HRV as a viable biomarker of disease severity has been recently proposed in several studies (11–13). In particular, we recently demonstrated that a key period during the temporal evolution of HRV in newborns with HIE coincided with the rewarming period (12). The current study underscores the importance of accounting for temperature in future analyses, to be sure that this observation reflects the disease evolution of HIE rather than changes in core temperature over the rewarming process.
Although prior studies have consistently shown reduced HRV in HIE newborns with poor outcomes (9–13), the mechanisms for this observation have not been fully elucidated. Decreased HRV may be attributable to direct subcortical or brainstem injury leading to autonomic dysfunction (38), the effects of asphyxia on the cardiovascular system (22), the presence of seizures (39–41), or likely a combination of these and other factors. As studies move forward toward more large-scale validation of HRV as a bedside biomarker in HIE, understanding potential confounding factors that can influence HRV under different clinical circumstances is crucial. Our study suggests that temperature variation in the moderate hypothermia range is a factor influencing HRV that needs to be addressed in future studies.
Several studies in adults have suggested a relationship between HRV and both ambient (27) and core body temperature (26, 28, 29). Studies in healthy preterm and term infants have focused on elevations in ambient temperature and its effect on HRV as a possible etiology for sudden infant death syndrome (30, 42). These prior studies have highlighted the complexity of the association between temperature and HRV, with one study describing nonlinear relationships and inverse patterns at temperature extremes (26). Few studies have investigated temperature effect on HRV in the setting of TH. Tiainen et al (28) reported increased HRV in adults undergoing hypothermia after cardiac arrest. Only one small study involving two newborns undergoing TH for HIE likewise reported a negative association between LF power and temperature (33). These investigators also found a negative association between HF power and temperature as well as a positive association between LF-to-HF ratio and temperature. We did not evaluate LF-to-HF ratio as recent reports have questioned whether this measure accurately reflects the sympathovagal balance as originally proposed (43). That we did not find a significant relationship between temperature and HF power may be attributable to the observation that HF power is less dynamic and appears to have less overall variability during this time period in newborns with HIE (12). This may also explain why no association was observed between RRi SD and temperature, as RRi SD provides an overall gross measure of variability rather than evaluating the contributions of specific inputs (e.g., sympathetic or parasympathetic) that may have differential relationships with temperature. To our knowledge, this is the largest study to date evaluating the relationship between HRV metrics and temperature in newborns undergoing cooling.
Our findings of increased HRV at lower temperatures are consistent with prior animal (25) and human studies (28, 29, 33) evaluating HRV in the temperature range of moderate TH. The temperature dependency of HRV may be explained via several possible mechanisms. As HRV has been described to be inversely related to heart rate (44), the change in HRV may be attributable to the relationship between heart rate (median RRi) and temperature alone. Alternatively, there may be direct effects of hypothermia on the myocardium that preserve HRV (25, 28). Finally, it is also possible that the reduction in HRV over the rewarming process reflects withdrawal of the therapeutic effect of hypothermia and may signify a potential benefit for continued hypothermia in some patients. Irrespective of the mechanisms by which body temperature interacts with HRV, our study supports that this relationship exists and may represent a clinically relevant covariate when considering HRV as a physiologic biomarker in neonates undergoing TH. Incorporation of patient temperature may be important as future HRV monitoring paradigms are developed for bedside application.
Several limitations of our study must be recognized. Not all patients contributed 10 hours of continuous data as some recordings were stopped due to clinical reasons. RDE retrieved data were incomplete for the time period of interest, or segments were excluded due to artifact. Although this may be a potential source of bias, the large number of observations provided by a continuous dataset mitigated any impact these missing data may have had on sample size for analyses. Although artifact in the ECG recordings could also impact results, our analytical approach incorporated a robust automated artifact rejection method (16). Finally, we collected temperature data from the medical record. This allowed for limited resolution (hourly) and the need to consider both esophageal and axillary temperatures for more complete and unbiased data. Although a recent study suggested that axillary temperatures have limited correlation with core temperature in babies undergoing hypothermia (45), axillary temperature remains the mainstay of temperature monitoring in newborns (46, 47) and has been reasonably correlated to core temperature in other studies (48, 49). Our results were similar when considering only available esophageal temperatures. Consistency of findings across these two analyses provides confidence in the relationships observed between temperature and HRV. Likewise, our sample size limited our ability to clearly elucidate the relationship between HRV metrics and temperature in infants with severe encephalopathy. Future studies are needed (and planned) with higher resolution core temperature data to further evaluate the relationship between temperature and HRV metrics in babies with moderate to severe HIE.
We thank Nickie N. Andescavage, MD, and Rhiya Dave, BA, for their assistance with data collection for this study.
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heart rate variability; hypoxic-ischemic encephalopathy; neonatal intensive care unit; temperature; therapeutic hypothermia