Matthias Keel

Sucrose reduces pain reaction to heel lancing in preterm infants: a placebo-controlled, randomized and masked study.

ABSTRACT: In term infants sucrose given by mouth has been reported to reduce duration of crying after a heel prick. This study was designed primarily to investigate the effect of sucrose administered orally immediately before heel lancing on the nociceptive reaction in preterm infants as assessed by change in heart rate and duration of crying. A secondary objective was to document changes in cerebral blood volume during acute pain. We used a randomized, masked, placebo-controlled, crossover trial in a neonatal intermediate care unit in a level 3 perinatal center. The patients studied were 16 preterm infants; birth weight, 900–1900 g; gestational wk, 27–34; corrected postmenstrual age at time of investigation, 33–36 wk. Each infant was assessed twice receiving 2 mL of sucrose 50% or 2 mL of distilled water in random order immediately before heel lance. Heart rate, thoracic movements, and transcutaneous blood gases were monitored continuously. Crying during the procedure was documented by a video-camera. A change in cerebral blood volume was assessed by near-infrared spectroscopy. We found the heart rate increased by a mean of 35 beats/min (bpm) after sucrose and 51 bpm after placebo (median difference 16 bpm, interquartile range 1–30 bpm, p = 0.005). Infants cried 67% of time after sucrose and 88% after placebo (median difference 10%, interquartile range 3–33%, p = 0.002). Cerebral blood volume decreased in 5 of 14 infants after sucrose and in 6 of 14 infants after placebo (difference not significant). We concluded that sucrose administered orally before a heel lance reduces the pain reaction in preterm infants. Response of cerebral blood volume to pain does not seem to be altered by sucrose.

The influence of a clear layer on near-infrared spectrophotometry measurements using a liquid neonatal head phantom

It is difficult to test near-infrared spectrophotometry instruments in vivo. Therefore we constructed a liquid phantom which mimics the neonatal head. It consists of a spherical 3.5 mm thick layer of silicone rubber simulating skin and bone and a 0.5 mm thick clear layer of polypropylene imitating cerebrospinal fluid. It acts as container for a liquid solution with Intralipid, 60 micromol l(-1) haemoglobin and yeast. The solution was oxygenated using oxygen and then deoxygenated by the yeast. From the instrumental (Critikon 2020) algorithm, we found that with increasing scattering (0.5%, 1%, 1.5% and 2% Intralipid concentration) the reading was increasingly offset from the expected value of 0 micromol l(-1) by 55.7, 68.6, 76.5 and 80.4 micromol l(-1) (oxyhaemoglobin) and 16.0, 24.4, 29.6 and 31.7 micromol l(-1) (deoxyhaemoglobin). This reduced the range of the oxygen saturation reading from the expected 100% to 31.5, 21.1, 14.3 and 11.5%. Haemoglobin concentration changes were increasingly underestimated by a factor of two to four. For a second algorithm based on the diffusion approximation the offsets were smaller: oxyhaemoglobin 11.4, 17.8, 22.5 and 25.1 micromol l(-1) and deoxyhaemoglobin 1.3, 3.4, 5.2 and 6.0 micromol l(-1). The range of the oxygen saturation reading was higher: 41.3, 29.2, 23.4 and 16.6%. Concentration changes were underestimated by a factor of six to ten. This study demonstrates the need to develop algorithms which take into consideration anatomical structures.

Cyclical fluctuations in blood pressure, heart rate and cerebral blood volume in preterm infants

Many recently published papers describe cyclical changes of cerebral circulatory variables, mainly in cerebral blood flow velocity (CBFV) performed with Doppler sonography. In this paper we focus on another important variable of cerebral circulation: on cerebral blood volume (CBV) measured by near infrared spectrophotometry (NIRS). In a retrospective analysis of NIRS measurements in 20 preterm infants (median 27 3/7 weeks of gestation), the dominating frequencies and prevalence of cyclical changes of CBV and its possible correlation with peripheral circulatory variables (mean arterial pressure and heart rate) was examined. In 19 out of the 20 infants cyclical changes of CBV were found within a frequency range of 2-4.7 cycles/min which is comparable to the results of the Doppler studies describing fluctuations in CBFV. A dominating frequency of heart rate (HR), was found only in 12 out of 20 infants, and it was with 2.1-3.8 cycles/min in a similar range compared to CBV. In mean arterial blood pressure (MABP), however we detected cycles with longer periods every 1-2.5 min in 14 out of 20 infants. There was a significant coherence between MABP/CBV and HR/CBV. The area under the coherence curve, however, was significantly larger between MABP and CBV as compared to HR and CBV (P = 0.0007, Wilcoxon signed-rank test).

MEASUREMENT OF ABSOLUTE CEREBRAL HAEMOGLOBIN CONCENTRATION IN ADULTS AND NEONATES

The concentration and saturation of the main oxygen carrier of the blood—the haemoglobin—may be an important clinical factor to judge the oxygenation of tissue. The brain is very sensitive to under-oxygenation. So far, the measurement of absolute cerebral haemoglobin concentration by near infrared spectrophotometry (NIRS) has not taken into account the contribution of skull and skin, which causes an underestimation by a factor of 3 [Owen-Reece, 1996] in adults.

Impact of Central, Obstructive and Mixed Apnea on Cerebral Hemodynamics in Preterm Infants

The objective of this study was to evaluate the effect of central, obstructive and mixed apnea on cerebral total hemoglobin concentration (tHb), which is analogous to cerebral blood volume, and to investigate whether tHb alterations correlate with bradycardia and arterial desaturation. Measurements were carried out on 17 preterm infants (gestational age 26-30 weeks) with frequent apneic events. Near infrared spectrophotometry (NIRS) was used to quantify changes in tHb. Respiration was monitored by chest movements using impedance pneumography and by nasal airflow using a thermistor. In addition, heart rate, arterial oxygen saturation, in each infant and esophageal pressure in 3 babies were continuously recorded. 130 apneic episodes of > 10 s duration showed four different patterns of tHb alterations: (1) no change in tHb (28%); (2) isolated decrease (35%); (3) isolated increase (12%), or (4) both combined, an initial decrease followed by an increase over the previous baseline level (25%). Obstructive apneic episodes were associated with a significantly greater maximum fall in tHb (median 11.5; 5th percentile 0 and 95th percentile 30.5 mumol/l) compared to mixed (4.9, 0 and 26.4 mumol/l) and central events (3.0, 0 and 14.0 mumol/l). Changes in tHb correlated with heart rate only in purely central apnea and were not reflected in arterial oxygen saturation in any type of apnea. Obstructive apnea was observed to have the strongest impact on tHb. As these tHb alterations may exacerbate or cause intraventricular hemorrhage, efforts must be made to prevent obstruction of upper airways and to focus monitoring on cerebral perfusion.

Comparison of three methods to measure absolute cerebral hemoglobin concentration in neonates by near-infrared spectrophotometry.

Three methods by which to determine absolute total cerebral hemoglobin concentration (tHb in micromol/L) by near-infrared spectrophotometry (NIRS) have evolved: (1) tHbo, requiring oxygenation changes and arterial oxygen saturation measurements as a reference using a relative NIRS algorithm, (2) tHbg, using a geometrical multidistance principle and (3) tHbgo, a combination of both. The aim of this study was to compare the three methods quantitatively. Sixteen clinically stable preterm infants with a mean gestational age of 29.6 (range of 25.1-36.4) weeks, birthweight of 1386 (680-2820) g and a postnatal age of 2.5 (0.5-6) days, who needed supplemental oxygen, were enrolled. The mean+/-standard deviation tHbg was 150.2+/-41.8 micromol/L (range of 61.6-228.9 micromol/L), the tHbo was 62.1+/-27.2 micromol/L (26.0-110.8 micromol/L) and the tHbgo was 89.3+/-45.6 micromol/L (26.5-195.9 micromol/L). The correlation coefficient among the three methods were tHbg and tHbgo r=0.736; tHbo and tHbgo r=0.938; tHbg and tHbo r=0.598. A multiple regression with variable selection by Mellows C(p) showed, that tHbg was correlated to the birthweight, the postnatal age, the heart rate and the pCO2 (r(2)=0.588), tHbo and tHbgo were associated with the hemoglobin concentration in the blood, the mean arterial blood pressure and the pCO2 (r(2)=0.493 and 0.406, respectively). The three methods (tHbg, tHbo, and tHbgo) give systematically different tHb readings and large intersubject variability.

Artifactual pulse-oximetry estimation in neonates

Two sources of artifactual pulse-oximetry estimation were investigated in 20 neonates. Increased pressure on tissue due to inappropriate sensor fixation was mimicked with a blood pressure cuff. The error in arterial oxygen saturation (pSO2) exceeded 2 SD (> 3%) in 25% subjects at 50 mm Hg which in an ancillary experiment was produced by 11 of 26 nurses fixing the sensor. Venous congestion at 30 and 40 mm Hg permitted normal detection of pulse rate but induced errors in pSO2 over 2 SD in 15% and 30% of subjects, respectively. Pulse-oximeter values need to be scrutinised for these common errors.

Tissue oxygen saturation measured by near infrared spectrophotometry correlates with arterial oxygen saturation during induced oxygenation changes in neonates.

The aim of this study was to compare quantitatively the changes in tissue oxygen saturation (TOS), determined by two algorithms (TOSc and TOSa) based on near-infrared spectrophotometry, to the changes in arterial oxygen saturation (SaO2) measured by pulse oximetry. TOSc is an algorithm derived by the manufacturer (Critikon) based on a modified Beer-Lambert law; TOSa, our own algorithm, uses the diffusion approximation of light transport for the semi-infinite boundary condition. Slow changes of more than 3% in SaO2 were carried out in 20 mechanically ventilated neonates by altering the inspired oxygen fraction. For each change the regression lines of TOSc versus SaO2, TOSa versus SaO2 and TOSc versus TOSa were calculatcd. For each infant the mcan slope, intercept and r2 of these lines were determined. In 18 preterm infants we obtained median 9.5 (range one to 13) measurements corresponding to a total of 166 measurements. The mean SaO2 was 91.6 (SD 2.3)%, TOSc was 64.7 (SD 7.2)% and TOSa was 71.4 (SD 11.0)%. Changes in TOSc and TOSa were strongly correlated to changes in SaO2 (r2 = 0.86 and r2 = 0.87). TOSc considerably but systematically underestimated the size of the change: delta TOSc = 0.49 delta SaO2. TOSa quantified changes reasonably correctly: delta TOSa = 0.90 delta SaO2. Changes in TOSc and TOSa were highly correlated (r2 = 0.98). These results are promising, but the large inter-individual variation requires further work.

Effect of aminophylline on cerebral haemodynamics and oxidative metabolism in premature infants

The effect of aminophylline on cerebral blood volume and oxidative metabolism in newborn infants was investigated with near infrared spectroscopy (NIRS). Thirteen mechanically ventilated premature infants who received aminophylline to facilitate weaning from the respirator were selected. Gestational age ranged between 26 and 34 weeks, postnatal age between 1 and 7 days and birth weight between 760 and 2300 g. A bolus of 6 mg aminophylline/kg body weight was infused within 2 min. NIRS was performed continuously across the head to monitor changes in cerebral blood volume and cytochrome c oxidase. Heart rate, transcutaneous carbon dioxide tension (tcpCO2) and arterial haemoglobin oxygen saturation (SO2) were recorded simultaneously. The infusion of aminophylline was associated with an increase in heart rate (median 12, interquartile range 5–20 beats per min,P=0.0004) and a drop in tcpCO2 (median −0.4, interquartile range −0.1 to −0.5 kPa,P=0.015). Oxygen saturation remained stable (±3%). A decrease in cerebral blood volume was measured with NIRS in 9/13 patients (median −0.15 ml/100g brain tissue, interquartile range +0.08 to −0.28,P=0.10). Oxidized cytochrome c oxidase decreased in 11/13 patients (median −0.27 μmol/l, interquartile range −0.19 to −0.44,P=0.01). Our findings demonstrate an immediate step-response of heart rate and tcpCO2 to aminophylline in premature infants. The simultaneous reduction of cytochrome c oxidase in the brain cannot be explained as a consequence of changes in tcpCO2 or changes in cerebral blood volume. We therefore speculate that aminophylline interferes directly with cerebral metabolism.

CO2 Reactivity of the Cerebral Hemoglobin Concentration in Healthy Term Newborns Measured by Near Infrared Spectrophotometry

CO2 reactivity of cerebral hemoglobin concentration was studied in 16 healthy term neonates on days 1 and 4 after birth using the near infrared spectrophotometry (NIRS) technique. The aim was to establish data on the physiological range of CO2 reactivity in healthy newborns and to investigate the influence of postnatal age on it. The CO2 reactivity measured by NIRS is expressed as the change of the total cerebral hemoglobin concentration (tHbR) per change of CO2 tension in µmol/l/kPa. We evaluated CO2 reactivity during increases and decreases of transcutaneous CO2 partial pressure and found in our methodological setting the data of the increases more reliable. In all infants but 1 we found a tHbR on day 1 with a mean value of 8.19 µmol/l/kPa (–1.39 to 18.87), in all infants on day 4 with a mean value of 9.54 µmol/l/kPa (2.76–25.88). There is a trend to higher values between day 1 and day 4 (difference = 2.25 µmol/l/kPa; p = 0.08). The noninvasive NIRS technique enabled us to test the cerebrovascular CO2 reactivity of the tHbR for the first time in healthy term newborns. Data on its physiologic range and variability are presented and compared to findings from ventilated infants and other age groups. As the CO2 reactivity might be an indicator for infants at risk of cerebral damage, it is necessary to have data on the physiological range of this parameter.