Tareq Al-Shargabi

Impaired cerebral autoregulation and brain injury in newborns with hypoxic-ischemic encephalopathy treated with hypothermia.

Impaired cerebral autoregulation may contribute to secondary injury in newborns with hypoxic-ischemic encephalopathy (HIE). Continuous, noninvasive assessment of cerebral pressure autoregulation can be achieved with bedside near-infrared spectroscopy (NIRS) and systemic mean arterial blood pressure (MAP) monitoring. This study aimed to evaluate whether impaired cerebral autoregulation measured by NIRS-MAP monitoring during therapeutic hypothermia and rewarming relates to outcome in 36 newborns with HIE. Spectral coherence analysis between NIRS and MAP was used to quantify changes in the duration [pressure passivity index (PPI)] and magnitude (gain) of cerebral autoregulatory impairment. Higher PPI in both cerebral hemispheres and gain in the right hemisphere were associated with neonatal adverse outcomes [death or detectable brain injury by magnetic resonance imaging (MRI), P < 0.001]. NIRS-MAP monitoring of cerebral autoregulation can provide an ongoing physiological biomarker that may help direct care in perinatal brain injury.

Heart rate variability in encephalopathic newborns during and after therapeutic hypothermia

Objective:To evaluate whether heart rate variability (HRV) measures are predictive of neurological outcome in babies with hypoxic ischemic encephalopathy (HIE).Study Design:This case–control investigation included 20 term encephalopathic newborns treated with systemic hypothermia in a regional neonatal intensive care unit. Electrocardiographic data were collected continuously during hypothermia. Spectral analysis of beat-to-beat heart rate interval was used to quantify HRV. HRV measures were compared between infants with adverse outcome (death or neurodevelopmental impairment at 15 months, n=10) and those with favorable outcome (survivors without impairment, n=10).Result:HRV differentiated infants by outcome during hypothermia through post-rewarming, with the best distinction between groups at 24 h and after 80 h of life.Conclusion:HRV during hypothermia treatment distinguished HIE babies who subsequently died or had neurodevelopmental impairment from intact survivors. This physiological biomarker may identify infants in need of adjuvant neuroprotective interventions. These findings warrant further investigation in a larger population of infants with HIE.

Detrended fluctuation analysis of non-stationary cardiac beat-to-beat interval of sick infants

We performed detrended fluctuation analysis (DFA) of cardiac beat-to-beat intervals (RRis) collected from sick newborn infants over 1–4 day periods. We calculated four different metrics from the DFA fluctuation function: the DFA exponents (>40 beats up to one-fourth of the record length), (15–30 beats), root-mean-square (RMS) fluctuation on a short-time scale (20–50 beats), and RMS fluctuation on a long-time scale (110–150 beats). Except , all metrics clearly distinguished two groups of newborn infants (favourable vs. adverse) with well-characterized outcomes. However, the RMS fluctuations distinguished the two groups more consistently over time compared to . Furthermore, RMS distinguished the RRi of the two groups earlier compared to the DFA exponent. In all the three measures, the favourable outcome group displayed higher values, indicating a higher magnitude of (auto-)correlation and variability, thus normal physiology, compared to the adverse outcome group.

Effects of regional brain injury on the newborn autonomic nervous system

OBJECTIVE Cerebral mapping of central autonomic nervous system (ANS)(1) function in mature animals and humans lateralizes sympathetic and parasympathetic influence predominantly to the right and left cerebral hemispheres, respectively. Spectral analysis of heart rate variability (HRV)(2) is an established measure of ANS function. We examined whether such lateralization is present in the term newborn. METHODS We retrospectively reviewed records of infants >36 weeks of gestation diagnosed with hypoxic ischemic encephalopathy (HIE).(3) We included infants with neonatal EEG and regional injury on brain MRI, which was scored using a schema. We extracted ECG signals from the EEG recording, but excluded periods of electrographic seizure activity to eliminate possible seizure influence on HRV. HRV was evaluated by spectral analysis in the high frequency (HF(4); 0.3-1 Hz) and low frequency (LF(5); 0.05-0.25 Hz) ranges, and the LF/HF ratio was examined to assess sympatho-vagal balance. The relation between the injured brain regions and HRV was studied using multiple linear regression models. RESULTS We studied 40 neonates with HIE. Injury to the right cerebral cortex (p=0.009) and right cerebellum (p=0.041) predicted a decreased LF/HF ratio. Injury to the left cerebral cortex (p=0.035) and left cerebellum (p=0.041) was associated with an increased LF/HF ratio. The association between brain injury location and the individual LF or HF spectral powers of brain injury did not reach significance. CONCLUSIONS Our data suggest that a functional lateralization for cerebral autonomic influence is established by term gestation.

Pattern of Brain Injury and Depressed Heart Rate Variability in Newborns with Hypoxic Ischemic Encephalopathy.

BackgroundDecreased heart rate variability (HRV) is a measure of autonomic dysfunction and brain injury in newborns with hypoxic ischemic encephalopathy (HIE). This study aimed to characterize the relationship between HRV and brain injury pattern using magnetic resonance imaging (MRI) in newborns with HIE undergoing therapeutic hypothermia.MethodsHRV metrics were quantified in the time domain (αS, αL, and root mean square at short (RMSS) and long (RMSL) timescales) and frequency domain (relative low-(LF) and high-frequency (HF) power) over 24–27 h of life. The brain injury pattern shown by MRI was classified as no injury, pure cortical/white matter injury, mixed watershed/mild basal ganglia injury, predominant basal ganglia or global injury, and death. HRV metrics were compared across brain injury pattern groups using a random-effects mixed model.ResultsData from 74 infants were analyzed. Brain injury pattern was significantly associated with the degree of HRV suppression. Specifically, negative associations were observed between the pattern of brain injury and RMSS (estimate −0.224, SE 0.082, P=0.006), RMSL (estimate −0.189, SE 0.082, P=0.021), and LF power (estimate −0.044, SE 0.016, P=0.006).ConclusionDegree of HRV depression is related to the pattern of brain injury. HRV monitoring may provide insights into the pattern of brain injury at the bedside.

Identification of QRS complex in non-stationary electrocardiogram of sick infants

BACKGROUND Due to the high-frequency of routine interventions in an intensive care setting, electrocardiogram (ECG) recordings from sick infants are highly non-stationary, with recurrent changes in the baseline, alterations in the morphology of the waveform, and attenuations of the signal strength. Current methods lack reliability in identifying QRS complexes (a marker of individual cardiac cycles) in the non-stationary ECG. In the current study we address this problem by proposing a novel approach to QRS complex identification. METHOD Our approach employs lowpass filtering, half-wave rectification, and the use of instantaneous Hilbert phase to identify QRS complexes in the ECG. We demonstrate the application of this method using ECG recordings from eight preterm infants undergoing intensive care, as well as from 18 normal adult volunteers available via a public database. We compared our approach to the commonly used approaches including Pan and Tompkins (PT), gqrs, wavedet, and wqrs for identifying QRS complexes and then compared each with manually identified QRS complexes. RESULTS For preterm infants, a comparison between the QRS complexes identified by our approach and those identified through manual annotations yielded sensitivity and positive predictive values of 99% and 99.91%, respectively. The comparison metrics for each method are as follows: PT (sensitivity: 84.49%, positive predictive value: 99.88%), gqrs (85.25%, 99.49%), wavedet (95.24%, 99.86%), and wqrs (96.99%, 96.55%). Thus, the sensitivity values of the four methods previously described, are lower than the sensitivity of the method we propose; however, the positive predictive values of these other approaches is comparable to those of our method, with the exception of the wqrs approach, which yielded a slightly lower value. For adult ECG, our approach yielded a sensitivity of 99.78%, whereas PT yielded 99.79%. The positive predictive value was 99.42% for both our approach as well as for PT. CONCLUSIONS We propose a novel method for identifying QRS complexes that outperforms common currently available tools for non-stationary ECG data in infants. For stationary ECG our proposed approach and the PT approach perform equally well. The ECG acquired in a clinical environment may be prone to issues related to non-stationarity, especially in critically ill patients. The approach proposed in this report offers superior reliability in these scenarios.

Changes in Autonomic Tone in Premature Infants Developing Necrotizing Enterocolitis

Background Necrotizing enterocolitis (NEC) is a complication of prematurity with a high mortality rate. Currently, there are no reliable biomarkers capable of identifying infants at risk for developing NEC. We sought to determine the autonomic nervous system antecedents of NEC in premature infants, using heart rate variability (HRV). Materials and Methods HRV was quantified by retrieving archived electrocardiogram (EKG) data from 30 premature infants from 4 days prior, through 4 days after, the clinical NEC diagnosis. HRV metrics were compared with those on the diagnosis day using the receiver operating characteristic (ROC) analysis. Results HRV metrics showed a depression of autonomic tone that preceded the clinical NEC diagnosis by 2 days, and which recovered to baseline by 2 days after diagnosis (area under the curve [AUC] < 0.7). The pattern of HRV change was significantly associated with the clinical severity of NEC (stage II vs. stage III). Conclusion Our studies suggest that readily accessible metrics of autonomic depression might expedite the diagnosis of NEC and its severity in a clinically meaningful manner. Clearly, these studies need to be extended prospectively to determine the diagnostic utility of this approach.

Effect of Temperature on Heart Rate Variability in Neonatal ICU Patients With Hypoxic-Ischemic Encephalopathy.

Objective: To determine whether measures of heart rate variability are related to changes in temperature during rewarming after therapeutic hypothermia for hypoxic-ischemic encephalopathy. Design: Prospective observational study. Setting: Level 4 neonatal ICU in a free-standing academic children’s hospital. Patients: Forty-four infants with moderate to severe hypoxic-ischemic encephalopathy treated with therapeutic hypothermia. Interventions: Continuous electrocardiogram data from 2 hours prior to rewarming through 2 hours after completion of rewarming (up to 10 hr) were analyzed. Measurements and Main Results: Median beat-to-beat interval and measures of heart rate variability were quantified including beat-to-beat interval SD, low and high frequency relative spectral power, detrended fluctuation analysis short and long &agr; exponents (&agr;S and &agr;L), and root mean square short and long time scales. The relationships between heart rate variability measures and esophageal/axillary temperatures were evaluated. Heart rate variability measures low frequency, &agr;S, and root mean square short and long time scales were negatively associated, whereas &agr;L was positively associated, with temperature (p < 0.01). These findings signify an overall decrease in heart rate variability as temperature increased toward normothermia. Conclusions: Measures of heart rate variability are temperature dependent in the range of therapeutic hypothermia to normothermia. Core body temperature needs to be considered when evaluating heart rate variability metrics as potential physiologic biomarkers of illness severity in hypoxic-ischemic encephalopathy infants undergoing therapeutic hypothermia.

Inflammatory cytokine response and reduced heart rate variability in newborns with hypoxic-ischemic encephalopathy

Objective:To determine whether systemic inflammation-modulating cytokine expression is related to heart rate variability (HRV) in newborns with hypoxic-ischemic encephalopathy (HIE).Study design:The data from 30 newborns with HIE were analyzed. Cytokine levels (IL-2, IL-4, IL-6, IL-8, IL-10, IL-13, IL-1β, TNF-α, IFN-λ) were measured either at 24 h of cooling (n=5), 72 h of cooling (n=4) or at both timepoints (n=21). The following HRV metrics were quantified in the time domain: alpha_S, alpha_L, root mean square (RMS) at short time scales (RMS_S), RMS at long time scales (RMS_L), while low-frequency power (LF) and high-frequency power (HF) were quantified in the frequency domain. The relationships between HRV metrics and cytokines were evaluated using mixed-models.Result:IL-6, IL-8, IL-10, and IL-13 levels were inversely related to selected HRV metrics.Conclusion:Inflammation-modulating cytokines may be important mediators in the autonomic dysfunction observed in newborns with HIE.

Baroreflex dysfunction in sick newborns makes heart rate an unreliable surrogate for blood pressure changes.

Background:Cerebral pressure passivity (CPP) in sick newborns can be detected by evaluating coupling between mean arterial pressure (MAP) and cerebral blood flow measured by near infra-red spectroscopy hemoglobin difference (HbD). However, continuous MAP monitoring requires invasive catheterization with its inherent risks. We tested whether heart rate (HR) could serve as a reliable surrogate for MAP in the detection of CPP in sick newborns.Methods:Continuous measurements of MAP, HR, and HbD were made and partitioned into 10-min epochs. Spectral coherence (COH) was computed between MAP and HbD (COHMAP-HbD) to detect CPP, between HR and HbD (COHHR-HbD) for comparison, and between MAP and HR (COHMAP-HR) to quantify baroreflex function (BRF). The agreement between COHMAP-HbD and COHHR-HbD was assessed using ROC analysis.Results:We found poor agreement between COHMAP-HbD and COHHR-HbD in left hemisphere (area under the ROC curve (AUC) 0.68) and right hemisphere (AUC 0.71). Baroreflex failure (COHMAP-HR not significant) was present in 79% of epochs. Confining comparison to epochs with intact BRF showed an AUC of 0.85 for both hemispheres.Conclusions:In these sick newborns, HR was an unreliable surrogate for MAP required for the detection of CPP. This is likely due to the prevalence of BRF failure in these infants.