Hyperimmunoglobulinemia D and periodic fever syndrome in children. Review on therapy with biological drugs and case report.

UNLABELLED: Hyperimmunoglobulinemia D syndrome (HIDS) is a rare, autosomal recessively inherited autoinflammatory disease caused by mutations in the mevalonate kinase gene. HIDS usually starts in infancy with recurrent fever episodes lasting 3-7 days and recurring every 4-6 weeks, with only partial symptom decrease in adulthood. Fever is typically accompanied by abdominal pain, vomiting, diarrhoea and cervical lymphadenopathy, and sometimes by skin and joint symptoms. Blood leukocytes and serum C-reactive protein are elevated during the episode, and in addition, high levels of interleukine-1 (IL-1), IL-6 and tumour necrosis factor (TNF) and respective soluble receptors have been measured. Instead, serum immunoglobulin D (IgD) is usually normal until 3 years of age. Currently, there is no established treatment for HIDS. Thus far, four children have been successfully treated with etanercep, TNF-alpha inhibitor, and three children with anakinra, IL-1 receptor antagonist. CONCLUSION: This review summarizes currently available data on the use biological medicines for HIDS in children. A Finnish 1.5-year-old patient with disease onset at 6 months of age, treated successfully with anakinra, is presented.

Effect of posture on spontaneous and thermally stimulated cardiovascular oscillations.

STUDY OBJECTIVE: The aim of the study was to investigate the effect of posture on thermally stimulated cardiovascular oscillations. DESIGN: The effect of increased gravitational stress (rising from sitting to standing position) on the thermally stimulated cardiovascular oscillations was measured in young male volunteers. Extensive cardiovascular function data were obtained using a cardiovascular investigation protocol. SUBJECTS: The volunteers were five fit young men, aged 20-21 years. EXPERIMENTS AND MAIN RESULTS: Cardiovascular changes from sitting to standing indicated increased sympathetic and decreased parasympathetic influence on heart and skin blood vessels; mean heart rate increased, beat to beat heart rate variability diminished, high frequency periodic heart rate variability decreased, low frequency heart rate oscillations and ratio of low frequency to high frequency heart rate variability increased, mean skin blood flow and oscillations of skin blood flow decreased (all p less than 0.05). Thermal skin stimulation at 0.01-0.10 Hz frequency increased both sitting and standing 0.10 Hz periodic heart rate variability (p less than 0.05), and 0.10 Hz thermal stimulation entrained the heart rate oscillations in sitting and standing subjects (p less than 0.05). In contrast, skin blood flow oscillations in sitting subjects decreased, while in standing subjects it increased during 0.10 Hz thermal stimulation compared to the corresponding prestimulus values (p less than 0.04). CONCLUSIONS: On the basis of previous physiological experiments, these results suggest coupling between thermoregulatory and 0.10 Hz reflex activities.

A non-invasive method for testing neural circulatory control in man.

Exaggerated cardiovascular responsiveness is common in young men and may cause non-specific symptoms and poor performance. Conventional autonomic function tests are not clinically useful. We have therefore designed a thermal entrainment method to evaluate sympathetic and parasympathetic cardiovascular function in subjects with dystonic symptoms and orthostatic intolerance. Oscillations of thermal gradient in the skin were produced by standardised periodic stimulation of the lower part of the arm with warm and cool water. Vasomotor activity of the skin induced oscillations of arterial blood pressure which were thought to be regulated by sympathetic and parasympathetic heart rate control and by oscillation of the sympathetically controlled peripheral vascular resistance. We tested the method in subjects with cardiovascular symptoms (n = 7) and controls (n = 7). At supine rest, the frequency response of the heart rate variability to the thermal stimulation at frequencies of 0.01, 0.02, 0.03 and 0.1 Hz was significantly different (p = 0.008) between symptomatic subjects and controls. The gain of the heart rate control was increased to 0.03 Hz [-1.3(SEM 0.5) dB v -3.8(0.8) dB, p = 0.068] and decreased at 0.1 Hz [-3.9(1.1) dB v -1.5(0.6) dB, p = 0.076] in the test group compared to the control group. At stimulus frequencies of less than 0.03 Hz the individual overall heart rate variability of the subjects with symptoms stayed below the mean control value, at 60(6) ms v 79(15) ms, p = 0.16. The cutaneous temperature oscillations at the site of stimulation, frequency response of the oscillations of the skin blood flow and respiration to the thermal stimulation, and mean heart rate were similar in the both groups. The results show that this thermal entrainment method quantifies the increased sympathetic and decreased parasympathetic cardiac control of subjects with dystonic symptoms.

Paclitaxel changes sympathetic control of blood pressure.

Paclitaxel has become part of standard therapy in the treatment of ovarian and breast cancer. Concern has been raised about the effects of paclitaxel on cardiovascular function. Therefore, this study of the effects of paclitaxel on autonomic cardiovascular control was initiated. Eighteen women treated for ovarian or breast cancer were examined with autonomic cardiovascular function tests, once before the treatment and once after the second course of paclitaxel. Heart rate and blood pressure variability and changes in heart rate and blood pressure responses to the tests were measured. Baroreflex sensitivity was calculated from the Valsalva manoeuvre non-invasively. Paclitaxel did not change heart rate variability at rest compared with the pretreatment level. However, medium frequency variability of blood pressure was smaller after treatment with paclitaxel. Paclitaxel treatment did not impair the heart rate and blood pressure responses to the autonomic function tests. The results do imply that paclitaxel alters sympathetic control of blood pressure. Nevertheless, paclitaxel does not appear to precipitate autonomic cardiac neuropathy.

Decreased heart rate variation in decerebration syndrome: quantitative clinical criterion of brain death?

Heart rate variation (HRV) was measured in 12 children with brain death. Computer analysis demonstrated an overall heart rate variation (RMSM) of 3.5 to 9.6 msec (mean, 6.0 msec). The respective figures for beat-to-beat variation (RMSSD) were 4 to 16 msec (mean, 7.7 msec). Normal infants (RMSM, 20 to 30 msec) and children (RMSM, 50 to 90 msec) and infants with respiratory distress syndrome (RMSM, 10 to 20 msec) have a clearly higher HRV than those with brain death. In all subjects a periodic component of the HRV with a cycle length of 5.9 +/- 0.26 seconds was discovered. In five patients an additional periodic component was found that corresponded exactly to the rate of artificial respiration. This study demonstrated the value of accurate digital techniques in the characterization of fixed heart rate in decerebration. This phenomenon could be considered one clinical criterion of brain death.

Children in sauna: cardiovascular adjustment.

Children's circulatory adjustment to a 10-minute heat stress in a climatic chamber was studied in 61 children and 20 adolescents and young adults. The thermal conditions corresponded to those of an ordinary Finnish sauna bath. In all subjects the rectal temperature and heart rate increased during the heat exposure (P less than .001). Systolic and diastolic blood pressures remained unchanged in sauna, but the systolic and especially the diastolic blood pressure decreased (P less than .001) in children less than 10 years of age immediately after the heat exposure; two vasovagal collapses developed. Cardiac output increased in all but the less than 5-year-old children (P less than .001). This was due to a significant decrease in stroke volume (32.9%) (P less than .001) in children less than 5 years old. Stroke volume declined slightly even in the older subjects. These changes indicate that the Finnish sauna bath puts great demands on a child's circulatory regulation. To avoid possible cardiovascular side effects, particularly small children should be supervised carefully during sauna bathing.

Blood pressure reactivity in patients with neurocirculatory asthenia.

The hemodynamic reactions of 30 young men with neurocirculatory asthenia (NCA) were compared to those of 30 healthy controls in isometric handgrip test, orthostatic test, and cold pressor test in order to study the regulation of the central circulation of NCA patients. The measurements were made using sphygmomanometry, ECG, and impedance cardiography. In the isometric handgrip test the heart rate and the diastolic and mean blood pressure increased slightly more (P less than 0.05) in the NCA group than in the controls. In the NCA group the blood pressure rise was, on average, due to an increase in the peripheral vascular resistance, while in the control group it was caused by an elevation in the cardiac output. In the orthostatic and cold pressor tests the hemodynamic alterations were quite similar in the two groups. It is concluded that the NCA patients have in the orthostatic and cold pressor tests a normal ability to elevate the blood pressure by increasing the peripheral vascular resistance. The lack of rise in the cardiac output during the isometric handgrip test in the NCA group is an abnormal reaction, the reason of which remains to be studied.

Heart-rate variability and SIDS. Examination of heart-rate patterns using an expert system generator.

In a prospective, population-based study, HRV was analyzed from 24-hr tape recordings made on 16 full-term and one preterm infant who had subsequently suffered SIDS and compared to similar data on 23 control infants (n of recordings, 44). In the SIDS group, heart rate was higher, and overall and beat-to-beat HRV (CV, CVS, respectively) were lower, than in the controls, but not significantly. Respiratory rate and respiratory HRV (by spectral analysis) were similar in both groups. Assuming that cardiorespiratory mechanisms of SIDS are multifactorial, we expected that several subgroups would be detected in both test groups. Therefore, the average data for each recording were subsequently examined by means of an expert system generator (ExTran, Intelligent Terminals Ltd., Edinburgh, UK). By rules induced with 25 nodes, the following results were obtained: 16/44 recordings were diagnosed as SIDS on the basis of (1) respiratory rate (RR) less than 33 and CV less than 3.46% (n = 8); (2) RR greater than 33, CVS less than 2.18%, and BW greater than 3,520 g (n = 4); and (3) RR greater than 33, CVS less than 2.18%, BW less than 3,520 g, HR greater than 136, and CV greater than 1.89% (n = 4). Seventeen of 44 were considered as non-SIDS when (1) RR was 33-47.4, CVS greater than 2.18%, and RSA less than 74.3 and (2) RR greater than 33, CVS less than 2.18%, BW less than 3,520 g, and HR less than 142. The remaining 11 cases required more complicated rules in order to be classified. This study shows that although the trend of increased HR and decreased HRV in the SIDS cases was statistically non-significant, an expert system program may be helpful in defining decision rules to identify cases of SIDS on the basis of cardiorespiratory data.

Docetaxel and autonomic cardiovascular control in anthracycline treated breast cancer patients.

BACKGROUND: Taxoids are new chemotherapeutic agents effective in the treatment of breast cancer. Paclitaxel treatment has been reported to cause some cardiac side effects and both paclitaxel and docetaxel to cause mild, mainly sensory, peripheral neuropathy. Autonomic function tests are sensitive measures of autonomic neuropathy and cardiac regulation. The purpose of this study was to find out whether docetaxel changes neural cardiovascular regulation in breast cancer patients previously treated with anthracyclines. PATIENTS AND METHODS: Nine women treated for metastatic breast cancer with docetaxel were studied prior to the docetaxel treatment and after the third or fourth course. Autonomic cardiovascular function tests were performed and heart rate and blood pressure variability were assessed with power spectrum analysis. RESULTS: Heart rate variability or the heart rate responses to the autonomic function tests did not change after docetaxel treatment. The blood pressure response to standing was enhanced and systolic blood pressure variability decreased after three to four cycles of docetaxel. CONCLUSIONS: Docetaxel treatment did not deteriorate vagal cardiac control in breast cancer patients after exposure to epirubicin. The observed changes in blood pressure responses suggest that docetaxel changes sympathetic vascular control. However, these changes seem to be related to altered cardiovascular homeostasis rather than peripheral sympathetic neuropathy.

Heart rate variability in infants subsequently suffering sudden infant death syndrome (SIDS).

To study the role of the autonomic cardiovascular control in SIDS the heart rate variability (HRV) was analysed from 24 tape recordings made from a prospective population-based study on 16 term and one preterm infant suffering SIDS and compared to similar data on 23 control infants matched on birthweight, gestation and postnatal age. The number of regular breathing segments was lower in the SIDS cases than in controls (P = 0.02). No significant differences were found between the SIDS cases and their controls for average heart rate, median breathing rate, indices of overall and beat-to-beat HRV. Neither were significant intergroup differences found when the subjects were divided into neonatal and postneonatal subgroups. Analysis of HRV by power-spectral techniques did not show any significant differences between SIDS cases and controls for the general distribution of power or for the respiratory HRV. Analysis of HRV did not differentiate infants destined to die of SIDS from surviving controls in the same population.

Increased amplitude modulation of continuous respiration precedes sudden infant death syndrome -detection by spectral estimation of respirogram.

The immaturity of the control of the autonomic nervous system has been suggested as one of the key factors in the pathophysiology of sudden infant death syndrome (SIDS). Therefore, the attenuated control of respiration may also cause more slow oscillatory breathing among infants at risk of SIDS. In this study, patterns of respiratory activity (RAV) and heart rate variability (HRV) were examined in Medilog-records prospectively obtained from 22 tape recordings made on 16 babies subsequently suffering from SIDS and from 22 matched control babies. A total of 248 signal segments, 120 s in duration, representing the state of regular breathing were visually selected for further analysis. The digitised signal sets were detrended, Fast-Fourier-transformed and autospectra as well as cross-spectra for the HRV and HRV were computed. The RAV and HRV were examined at two spectral bands: (1) a low frequency (LF) band 0.03-0.17 Hz (1.8-10 cycles/min) and (2) a high frequency (HF) band 0.3-1.3 Hz (18-90 cycles/min). Different parameters of each band were tested in the spectral analysis of cardiorespiratory control. The LF/HF-ratio of the spectral peak area of the respiratory activity and the LF/HF-ratio of the spectral band area of the respiratory activity were greater in the SIDS group when compared to the controls. No significant intergroup differences were found in the parameters of HRV, or the cross-spectral parameters. Interestingly, the technique appeared helpful in displaying that the victims of SIDS had a significantly greater amount of slow oscillation in the continuous respiratory signal (1.05+/-1.89 vs. 0.41+/-0.57, P=0.02). In the victims of SIDS the respiratory control system seems to be less stable and cause more slow oscillatory breathing and this can be detected using spectral analysis of respiratory activity even during breathing that visually seems to be regular.

Computer analysis of heart rate variation and breathing movements in fetal lambs.

A quantitative method for studying the frequency-specific relationships between heart rate (HR) and fetal breathing movements (FBM) was developed. The reactivity of periodic HR variation in relation to FBM was investigated by means of power spectral analysis. Seven fetal lambs were studied during the third trimester of gestation using a chronic animal model. HR variability increased at the rate of FBM, as shown by an increase of spectral density at > 0.35 Hz in the HR autospectrum and in the cross-spectrum of HR and respirogram, as well as by an increase in the short-term variability index CVS. FBM were associated with the increased HR variation in all but the lowest frequency bands (0.07-1.0 Hz). Although respiratory sinus arrhythmia was found, only 10 per cent of the total HR variability and 25 per cent of the joint-density of HR and respirogram appeared at > 0.35 Hz during FBM. The greatest variation in both the HR and respirogram spectra appeared at < 0.07 Hz. Although the low-frequency variability of HR and respirogram was simultaneous, it was on the whole not synchronised. The existence of multiple control systems that simultaneously link the cardiac and respiratory control mechanisms to each other in the fetal lamb is postulated.

Beta-adrenergic control and inter-relationships between heart rate and blood pressure in neonatal lambs.

Our aim was to develop a signal analysis method for revealing interrelationships between heart rate and blood pressure and for displaying the influence of autonomic nervous control on these signals in a chronic lamb model. A chronically instrumented neonatal lamb model was made to record ECG and direct arterial blood pressure (N = 15). Continuous two-minute recordings of blood pressure (BP) and ECG were digitised. The instantaneous heart rate signal (IHR) was derived from the ECG. The IHR and BP signals were bandpass filtered. Autospectra, cross-spectra, coherence spectra and phase spectra for the signals were computed to study the relative magnitudes and inter-relationships of the cardiovascular signals under normal conditions and during beta-adrenergic blockade. It was noted that both in the BP and IHR there were oscillations at the frequency of less than 0.1 Hz and also at the respiratory rate around 0.6 Hz. Beta-blockade reduced the oscillations of the IHR in less than 30-day-old lambs. It did not affect the coherence spectra or the phase lag between the signals. During quiet sleep the variability of blood pressure was decreased. In over-30-day-old-lambs the beta-blockade did not affect the variabilities of the cardiovascular parameters. These findings indicate that in neonatal lambs the sympathetic control system is a major regulator of cardiovascular interactions.

Individual relationship between heart rate and electromechanic systole in orthostatic test during autonomic blockade.

The aim of this work was to investigate the usefulness of the individual regression coefficients between the HR and the Q-A2 when studying their relationship during simultaneous changes in afterload and preload in combination with autonomic blockade. Twelve healthy male volunteers were studied in an orthostatic test done four times: without drugs (control test), after atropinization, after beta-blockade, as well as after combined beta-blockade and atropinization. The individual regression coefficients showed great inter-individual variation, and in average they were not significantly different in the four tests. However, it was observed that during the control test four, during the atropinization eight, during the beta-blockade three and during the combined beta-blockade and atropinization five individual regression coefficients were greater than -2.1, which is the regression coefficient used for the rate correction of the Q-A2 in males in the Weissler formula. It seems to use that the individual regression coefficents are useful in the evaluation of the relationship between the HR and the Q-A2 in pharmacological or physiological interventions, in which the intra-individual variation is great, and in which the number of subjects is often so small that group regressions are not very informative.

Rapid changes in rate-corrected and uncorrected systolic time intervals during cold pressor test.

The changes in heart rate and systolic time intervals were studied in a group of 10 young healthy male volunteers during immersion of their hand in ice water for 1 min. The heart rate and systolic time intervals were measured from electro-, phono-, and impedance cardiograms in the standard way. When the cold immersion was done in the supine position the left ventricular ejection time (LVET) and the electromechanic systole (Q-S2Tc) shortened, and when corrected for the heart rate the Q-S2Tc lengthened in the beginning of the immersion. In the head-up position the Q-S2T shortened in the beginning of the immersion while the rate-corrected systolic time intervals remained unchanged. Most of the changes in the systolic time intervals disappeared before the last quarter of the cold immersion. It was observed that during the cold immersion the linear regression coefficients between the heart rate and the Q-S2T in the supine position as well as between the heart rate and the LVET, Q-S2T and the PEP in the head-up position were greater than the regression coefficients used in the rate correction.

Heart rate variability, cardiac mechanics, and subjectively evaluated stress during simulator flight.

The effects of a simulator flight task on the heart rate variation (HRV) and hemodynamic variables were studied in nine pilots with instrument flight ratings. An electrocardiogram (ECG), phonocardiogram (PCG), and impedance cardiogram (ICG) were recorded continuously during three successive flights. Indices of HRV, power spectra, and autocorrelograms were computed from the R-R interval signal. Stroke volume (SV), cardiac output (CO), and systolic time intervals (STI) were determined by means of the ECG, PCG, and ICG. A scaling method for a subjective evaluation of tiredness, effort, and success during the flight was used. The repeats of the flight task decreased the heart rate (HR), CO, and cardiac index (CI). The different phases of the flight altered the HR (mean 97 min-1, S.E.M. 4 min-1), total HRV (RMSM) (mean 33 ms, S.E.M. 5 ms), and the periodic HRV. Subjectively, the pilots felt only moderate stress. The subjectively evaluated tiredness was significantly associated with the STI. Moderate informative stress in the flight simulator affected the chronotropic parameters of the heart. The inotropic state of the heart was not affected by the different phases of the flight but possibly by the diminishing sympathetic drive with accommodation during the repeats.

High resolution ECG changes among Finnish pilots.

BACKGROUND: Abundant appearance of late potentials registered by high resolution ECG (HR-ECG) has been shown to predict a risk for cardiac arrhythmia. The aim of this study was to evaluate the appearance of normal and abnormal late potentials in a group of Finnish private and commercial pilots. METHODS: Standard 12-lead ECG and 40-250 Hz band-pass filtered HR-ECG were recorded in 168 healthy male pilots. The following parameters were estimated: the root-mean-square voltage in the terminal 40 ms (RMS40), the total filtered QRS duration (FQRSD) and the duration of terminal high frequency low amplitude signal (HFLAD) of less than 40 microV in the filtered QRS. RESULTS: Age (38 +/- 12 yr) and height (179 +/- 6 cm) had a significant (p < 0.005) and independent association with the total filtered QRS duration. No such correlations were observed for RMS40 or HFLAD. Mean +/- SD for RMS40 was 35.3 +/- 15.4 microV, for FQRSD 114.6 +/- 6.8 ms and for HFLAD 31.0 +/- 7.9 ms. Smokers tended to have longer late potentials (HFLAD) than non-smokers. Fasting blood glucose had a significant (p < 0.05) positive correlation with HFLAD. Serum cholesterol level had no correlation with the HR-ECG parameters. Age and height of the subject were associated with the total QRS duration as follows: FQRSD (ms) = -9.7* log age (yr) + 0.2*height (cm) + 94.6.