Sex differences in cardiac and autonomic response to clinical and experimental pain in LBP patients.

Rehabilitation professionals are currently using heart rate (HR) in order to assess the sincerity of effort in certain evaluations. It has been shown that a relation exists between HR and pain but no study has measured cardiac response during both clinical and experimental pain among a patient population using an intra-subject design. Thirty patients with low back pain (LBP) participated in this study including 16 men. Clinical pain was induced by applying a postero-anterior pressure (PA) on a painful lumbar segment for 15 and 30s in order to reproduce the patient's typical LBP at an intensity ranging between 50 and 70/100. Experimental pain was induced with a 15s thermal stimulus at a temperature which reproduced the same pain intensity as the 15s PA. For both reproduced clinical pain durations, we observed a rise in HR ranging between 8.5% and 12.67%. However, unlike men, women's cardiac response failed to show a constant rise in HR during the 30s PA. For all subjects, the rise in HR was much lower during the experimental pain condition (p<0.001), reaching only 5%. On the other hand, galvanic skin responses were significantly higher during the experimental pain condition (p<0.001). During this same condition, women also had a greater rise in galvanic skin responses than men (p=0.04). Finally, a significant correlation was found between both types of pain. These results suggest that pain induced during a clinical evaluation will produce a significant HR augmentation. However, heart rate variability analysis showed greater sympathetic cardiac regulation for men. The sex differences observed in this study call for caution when interpreting HR during pain assessment.     

急性肝炎患者自主神经功能变化的研究

目的 观察急性肝炎患者自主神经功能的变化,探讨急性肝炎患者胃动力异常的病理机制.方法 石家庄市第一医院消化内一科2010年10月至2011年9月就诊的急性肝炎患者70例,其中男40例,女30例.健康志愿者35名,男20名,女15名.采用24h动态心电图,记录24h、早餐前后各1h的动态心电图检测结果,进行心率变异分析,测定自主神经功能.结果 急性肝炎组24h总体自主神经功能活动异常,表现为交感神经活跃,SDNNindex（60.07±13.54vs.77.82±19.74）,ULF（269 785.9±19 774.27vs.316 798.1±33 428.03）差异有统计学意义（P＜0.05）;迷走神经功能减弱,RMSSD（38.92±12.25vs.24.63±8.46）,HF（329 951.9±189 775.89vs.261 198.79±116 361.79）差异有统计学意义（P＜0.05）;交感迷走平衡失调（0.96±0.53vs.2.01±0.83）,差异有统计学意义（P＜0.05）;餐前与餐后自主神经活动异常,表现为交感神经功能亢进,SDNNindex为77.29±20.54vs.205.92±78.66,迷走神经功能减弱,RMSSD为34.59±11.29vs31.09±9.87.结论 急性肝炎患者存在自主神经功能异常,可能与急性肝炎患者胃动力障碍有关.     

The effect of remote ischemic postconditioning on autonomic function in patients with acute ischemic stroke: A Randomized Controlled Trail

ObjectiveThe evidence for the effect of remote ischemic postconditioning(RIpostC) on autonomic function in patients with acute ischemic stroke(AIS) is lacking and the neural mechanism underlying the protection of RIpostC remains speculative. This trial was aimed to evaluated the efficiency of RIpostC on autonomic function in AIS patients.DesignOne hundred and six AIS patients were included in this prospective, randomized, placebo-controlled trial. Patients in intervention group (n = 57) received 4 cycles of alternating inflation (cuff inflation to 200 mmHg) and deflation for 5 min on healthy upper arm once a day for 30 days. The control group underwent a sham inflation and deflation cycles. Autonomic function was evaluated by heart rate variability (HRV).ResultsAll HRV parameters except for the ratio of low frequency to high frequency (P = 0.101) increased significantly with time (P < 0.001) in the two groups. The value of standard deviation of all normal R-R intervals(SDNN) and high frequency at day7 and day30 and the value of the percent of difference between adjacent normal R-R intervals (pNN50) at day 30 in RIpostC group was significantly higher than that of the sham-RIpostC group(P < 0.05). A significant time-by-group interaction was observed in SDNN、pNN50、and high frequency over time between two groups (P < 0.05).Conclusions30-day RIpostC could improve autonomic function in AIS patients through the enhancement of the total autonomic nerve activity and vagus nerve activity. The mechanism of RIpostC mediating autonomic function needs to be further investigated.     

交感皮肤反应在周围神经疾病中对自主神经功能的评价

目的 评估在周围神经疾病中交感皮肤反应的检查价值。方法 对１４例周围神经疾病患者进行交感皮肤反应的检测,并与２０例健康志愿者进行对比分析。结果 对照组中２０例均能清晰引出波形,患者组中６例未引出波形,３例波幅明显下降,异常率占６４％。结论交感皮肤反应是一种简便易行、无创性的自主神经功能检测方法,具有一定的临床实用价值。     

Effects of isometric handgrip training on cardiac autonomic profile: A systematic review and meta‐analysis study

Meta‐analyses have shown that isometric handgrip training reduces blood pressure in normotensive and hypertensive subjects. However, the effects on cardiac autonomic modulation are still controversial. Thus, the aim of this systematic review and meta‐analysis was to analyse the effects of isometric handgrip training on cardiac autonomic modulation in normotensive and hypertensive subjects. For this, Medline, Cinhal, Embase, Spordiscus and PEdro were searched for relevant studies published until December 2018. Randomized controlled trials investigating the effect of isometric handgrip training on heart rate variability parameters were considered eligible. Parameters were obtained in time (standard deviation of all the RR intervals‐SDNN, root mean square of successive differences between the normal adjacent RR intervals‐RMSSD and the percentage of adjacent intervals with more than 50 ms‐PNN50) and frequency domain (low frequency‐LF, high frequency‐HF and sympathovagal balance‐LF/HF). Mean difference (MD) and 95% confidence interval (95% CI) were calculated using an inverse variance method with a random effects model. Seven trials were included in the systematic review and meta‐analysis, totalling 86 participants. No significant effect was observed in heart rate variability parameters after isometric handgrip training (4 trials to SDNN: MD = ?1.44 ms and 95% CI = ?8.02, 5.14 ms; RMSSD: MD = ?1.48 ms and 95% CI = ?9.41, 6.45 ms; PNN50: MD = 0.85% and 95% CI = ?1.10, 2.81%; 7 trials to LF: ?0.17 n.u. and 95% CI = ?6.32, 5.98 n.u.; HF: MD = 0.17 n.u. and 95% CI = ?5.97, 6.30 n.u.; and LF/HF: MD = 0.13 and 95% CI = ?0.34, 0.59). In conclusion, current literature indicates that isometric handgrip training does not improve heart rate variability.     

Abnormal autonomic cardiac response to transient hypoxia in sickle cell anemia

The objective of this study was to non-invasively assess cardiac autonomic control in subjects with sickle cell anemia (SCA) by tracking the changes in heart rate variability (HRV) that occur following brief exposure to a hypoxic stimulus. Five African-American SCA patients and seven healthy control subjects were recruited to participate in this study. Each subject was exposed to a controlled hypoxic stimulus consisting of five breaths of nitrogen. Time-varying spectral analysis of HRV was applied to estimate the cardiac autonomic response to the transient episode of hypoxia. The confounding effects of changes in respiration on the HRV spectral indices were reduced by using a computational model. A significant decrease in the parameters related to parasympathetic control was detected in the post-hypoxic responses of the SCA subjects relative to normal controls. The spectral index related to sympathetic activity, on the other hand, showed a tendency to increase the following hypoxic stimulation, but the change was not significant. This study suggests that there is some degree of cardiovascular autonomic dysfunction in SCA that is revealed by the response to transient hypoxia.     

Physical activity and cardiac autonomic dysfunction in patients with chronic obstructive pulmonary disease: A cross-sectional analysis

BackgroundThe cardiac autonomic function in patients with chronic obstructive pulmonary disease (COPD) has been poorly studied.ObjectivesWe aimed to 1) describe the cardiac autonomic function assessed by heart rate recovery (HRR) and chronotropic response (CR) during a 6-min walk test (6MWT) and afterward and 2) estimate the association of physical activity with HRR and CR in COPD patients.MethodsThis cross-sectional analysis included 320 patients with mild to very severe COPD. Physical activity (steps, time in any/moderate-to-vigorous/vigorous physical activity, intensity and sedentary time) was measured during 1 week by accelerometer. CR and HRR were measured during a 6MWT and 5 min after, respectively, and their association with physical activity parameters was estimated by multivariable linear regression models.ResultsPatients were 82% male and had a mean (SD) age 68 (8) years, post-bronchodilator FEV₁ 57 (18) % predicted, and walked a mean of 7716 (4139) steps/day. HRR was slow until 5 min after the 6MWT; the mean (SD) HRR was 15 (10), 22 (11), 25 (12), 25 (12) and 27 (12) bpm after 1, 2, 3, 4 and 5 min, respectively. The mean (SD) CR was 35% (16). After adjusting for relevant confounders, time in vigorous physical activity was significantly associated with a fast decrease in HRR (p = 0.044) and an increase in CR (p = 0.021). We found no independent association for other physical activity parameters.ConclusionA cardiac autonomic dysfunction is present in patients with mild to very severe COPD and is inversely related to the practice of vigorous physical activity.Trial registration ClinicalTrials.gov NCT01897298.     

Susceptibility to neuromediated syncope after acute myocardial infarction

BACKGROUND: Syncope after acute myocardial infarction (AMI) is a common clinical problem. It may be hypothesised that remodelling and neurohormonal changes following AMI may predispose to neuromediated syncope. DESIGN: To address this issue we prospectively evaluated the incidence of positive results of head-up tilt-table testing in 40 patients following AMI and 40 age and sex matched controls without a history of syncope. The mechanisms of tilt-induced changes in autonomic tone were assessed using spectral analysis of heart rate variability. The patients were followed-up for one year. RESULTS: Positive results of tilt-test occurred in 4 (10%) controls and 13 (33%) AMI patients (P = 0.01). No significant differences in sympathovagal interaction (assessed by a low frequency/high frequency ratio) were detected between the groups before tilting (2. 9 +/- 1.9 vs. 3.1 +/- 2.2; NS). However, dynamic changes of this parameter differed significantly during the first 5 symptomless minutes of the active phase of tilt-test. The ratio increased in the majority of controls (87%) and decreased in the majority of patients (62%) (P < 0.0001). During one year follow-up, syncope or presyncope occurred in 10 (25%) AMI patients but did not occur in any control subject (P < 0.001). The sensitivity, specificity and predictive accuracy of an early tilt-test after AMI for the prediction of syncope or presyncope was 70%, 80% and 78%, respectively. CONCLUSION: Patients after AMI are prone to neuromediated reactions. Sympathetic withdrawal seems to be the most likely mechanism of syncope. The role of tilt testing for identification of patients susceptible to syncope or presyncope after AMI needs further investigation.     

Systemic autonomic involvement in episodic cluster headache: a comparison between active and remission periods

In this study we compared systemic autonomic involvement in episodic cluster headache during active and silent periods. Seventeen patients were studied with sympathetic skin response, lying to standing test, Valsalva manoeuvre, deep breathing test and orthostatic hypotension evaluation. Each of them underwent these tests during active and silent periods. Values were then compared with normal controls. Our data show a parasympathetic, but not sympathetic, involvement. Moreover, this impairment seems to be “chronic”, as it persists beyond the active period.     

Comment on 'Abnormal autonomic cardiac response to transient hypoxia in sickle cell anemia'

Our recent results support the suggestions made by Sangkatumvong et al regarding autonomic dysfunction in sickle cell anemia.     

Chronotropic incompetence response to exercise in congestive heart failure,relationship with the cardiac autonomic status

In chronic congestive heart failure (CHF), attenuated heart rate response to exercise, a manifestation of chronotropic incompetence (CI), contributes to limiting exercise capacity. The present study was thus conducted to evaluate the respective role of chronic attenuation of cardiac vagal tone associated with depressed baroreflex sensitivity or affected cardiac sympathetic responsiveness in CHF patients with CI. Spontaneous cardiac baroreflex sensitivity (BRS) assessed by sequence method and spectral‐ and time‐domain analysis of heart rate variability (HRV) were analysed in 21 chronic CHF patients. All patients performed a symptom‐limited exercise test with measurement of gas exchange. Chronic incompetence which was defined as failure to achieve ≥80% of the heart rate reserve (%HRR) given by (HR_peak – HR_rest)/(predictive maximal heart rate – HR_rest) was observed in 14 (66%) patients. There was no significant difference in age, heart rate, peak oxygen uptake or left ventricular ejection fraction between the patients with and without CI. Although there was no significant difference in BRS, low frequency power of HRV in normalized units (LFnu) and SDNN were significantly lower in CI patients. Percentage of HRR correlated significantly with LFnu on 15 min (r=0·64, P<0·005) and, with LFnu on 24 h (r=0·52, P<0·01), SDNN (r=0·48, P=0·03) and SDANN (r=0·48, P=0·03), but not BRS (r=0·04, P=NS). Autonomic nervous system derangement is a complex process in CHF. The role of basal depressed cardiac sympathetic tone seems to contribute more closely than depressed baroreflex sensitivity to the impaired heart rate response to exercise frequently observed in CHF patients.     

Peripheral autonomic potentials in primary headache and drug-induced headache

Autonomic functions of different primary headache types have been investigated in several studies, most of them analyzing cardiovascular reflex mechanisms or biochemical changes. The results are contradictory; only in tension-type headache and in cluster headache has a sympathetic hypofunction been shown in a preponderance of studies. We analyzed the peripheral autonomous potentials (PAPs) in different primary headache types and in drug-induced headache and compared the results with those of healthy subjects and of patients with low back pain. Latencies of PAPs were significantly increased in all headache types but not in low back pain; amplitudes of PAPs did not show significant differences compared to healthy subjects. Patients with a long duration of drug abuse had increased PAP latencies, whereas patients with a high number of migraine attacks per year had decreased latencies. Our data suggest that sympathetic hypofunction as measured by PAP latencies is a general phenomenon in headache but not in all pain syndromes. Drug abuse leads to an increase of this hypofunction. While measuring PAPs is not an appropriate method by which to differentiate between headache disorders, it allows assessment of autonomic disturbances in primary and drug-induced headache.     

Angiotensin AT1 receptor over-expression in hypercholesterolaemia

Angiotensin II mediates most of the biological effects of the renin-angiotensin system (RAS), such as vasoconstriction and cell proliferation, via stimulation of the angiotensin II type 1 (AT1) receptor. The AT1 receptor plays a central role in the pathogenesis of atherosclerosis and hypertension. In parallel, hypercholesterolaemia is a major risk factor for the development and progression of cardiovascular diseases. The underlying molecular events, however, are understood only partially. An important mechanism may be the interaction between hypercholesterolaemia and AT1 receptor expression in vascular tissue. Low-density lipoprotein (LDL) cholesterol leads to a profound increase in AT1 receptor expression in cultured vascular smooth muscle cells as well as in hypercholesterolaemic rabbits. This up-regulation is associated with an enhanced functional response upon stimulation with angiotensin II. Over-expression of the vascular AT1 receptor can also be observed in hypercholesterolaemic men and is prevented by treatment with 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors. These findings may explain why hypercholesterolaemia is frequently associated with hypertension and why blockade of the RAS attenuates the progression of atherosclerosis.     

Effect of Simvastatin on markers of triglyceride-rich lipoproteins in familial hypercholesterolaemia

BACKGROUND: We have previously shown elevated fasting plasma concentrations of intestinal remnants, as reflected by apolipoprotein (apo) B-48 and remnant-like particle-cholesterol (RLP-C) in patients with heterozygous familial hypercholesterolaemia (FH). We now investigate the effect of an HMG-CoA reductase inhibitor (simvastatin) on chylomicron remnant metabolism using the measurement of fasting apoB-48 and RLP-C in FH patients after long- and short-term simvastatin therapy and after a wash-out period. We also piloted the response of a breath test, involving the measurement of the fractional catabolic rate (FCR) of an intravenously injected chylomicron remnant-like emulsion labeled with cholesteryl (13)C-oleate. METHODS: Fifteen FH patients were studied after > 6 months 40 mg day(-1) simvastatin treatment (long-term), a wash-out period (4 weeks), and 4 weeks of simvastatin treatment (short-term). Apolipoprotein B-48 was determined by SDS-PAGE and Western blotting/enhanced chemiluminescence and RLP-C by an immunoseparation assay. The FCR of the chylomicron remnant-like emulsion was determined from the appearance of (13)CO(2) in the breath and by multicompartmental mathematical modelling. RESULTS: Both long- and short-term treatment with simvastatin were associated with decreases in the plasma concentration of apoB-48 (P < 0.05) and RLP-C (P < 0.001), but there was no significant change in the FCR of the emulsion. CONCLUSIONS: We suggest that long- and short-term treatments with simvastatin have comparable effects in decreasing the plasma concentration of triglyceride-rich remnants in heterozygous FH, as measured by fasting apoB-48 and RLP-C. The mechanisms for this may involve decreased production of hepatic and possibly intestinal lipoproteins, and/or up-regulation of hepatic receptor clearance pathways, but these changes are apparently not associated with a change in remnant clearance as measured kinetically by the (13)CO(2) breath test.     

炎症性肠病患者的自主神经功能改变

目的探讨炎症性肠病(IBD)患者的自主神经功能改变状况。方法分析2012年1月至2014年2月在消化内科接受住院或是门诊治疗的IBD患者[溃疡性结肠炎(UC)和克罗恩病(CD)]的临床资料,并选取正常体检者作为对照组。两组受试者均行迷走副交感神经和交感肾上腺能神经功能的检查。结果共纳入研究对象105例,其中IBD患者70例(UC患者38例,CD 32例),对照组35例。IBD患者的卧立位心率变化值均显著低于对照组,差异具有统计学意义(t=4.025,P0.001);两组受试者的瓦氏指数相比差异无统计学差异(t=0.400,P=0.690)。IBD组患者的卧立位血压差值显著高于对照组(t=2.845,P0.001);IBD组患者的握力实验血压差值均显著低于对照组,差异具有统计学意义(t=8.273,P0.001)。结论 IBD患者相对于正常对照组,其交感肾上腺素能神经系统功能明显增强,而迷走副交感神经功能相对有所减弱。     

Altered cardiovascular autonomic regulation after salmeterol treatment in asthmatic children

The effects of therapeutic 4 weeks' inhaled salmeterol treatment on the cardiovascular and respiratory autonomic nervous regulation was studied in 11 asthmatic children using inhaled corticosteroid medication. The study followed a randomized, double-blind, placebo-controlled cross-over design. The salmeterol dose was 50 μg twice daily. The 4-week salmeterol treatment increased baseline heart rate, low-frequency/high-frequency (LF/HF) variability ratio of R–R intervals, LF variability of systolic arterial pressure (SAP) and maximum tidal volume during the deep breathing test, as well as morning and evening peak expiratory flow (PEF) values. The 4-week salmeterol treatment decreased baseline HF variability of R–R intervals. As a response to the acute 600 μg of salbutamol, the changes in heart rate, HF variability of R–R intervals and diastolic blood pressure were significantly smaller after 4 weeks' salmeterol treatment. In conclusion, 4 weeks' therapeutic salmeterol treatment decreases basal cardiovagal reactivity, increases sympathetic dominance in the cardiovascular autonomic balance and improves pulmonary function. A tolerance develops in the cardiovascular response but not in the bronchodilatory response.     

Middle cerebral artery blood flow velocity in response to lower body positive pressure

Lower body positive pressure (LBPP) has been used in the treatment of haemorrhagic shock and in offsetting g‐force induced fluid shifts. However, the middle cerebral artery blood flow velocity (MCAv) response to supine LBPP is unknown. Fifteen healthy volunteers (mean ± SD: age, 26 ± 5 year; body mass, 79 ± 10 kg; height, 174 ± 9 cm) completed 5 minutes of 20 and 40 mm Hg LBPP, in a randomized order, separated by 5 minutes rest (baseline). Beat‐to‐beat MCAv and blood pressure, partial pressure of end‐tidal carbon dioxide (P_ETCO₂) and heart rate were recorded and presented as the change from the preceding baseline. All measures were similar between baseline periods (all P>0·30). Mean arterial pressure (MAP) increased by 7 ± 6 (8 ± 7%) and 13 ± 7 mm Hg (19 ± 11%) from baseline during 20 and 40 mm Hg (P<0·01), respectively. The greater MAP increase at 40 mm Hg (P<0·01 versus 20 mm Hg) was mediated via a greater increase in total peripheral resistance (P<0·01), with heart rate, cardiac output (Model flow) and P_ETCO₂ remaining unchanged (all P>0·05) throughout. MCAv increased from baseline by 3 ± 4 cm s^?1 (5 ± 5%) during 20 mm Hg (P = 0·003), whilst no change (P = 0·18) was observed during 40 mm Hg. Our results indicate a divergent response, in that 20 mm Hg LBPP‐induced modest increases in both MCAv and MAP, yet no change in MCAv was observed at the higher LBPP of 40 mm Hg despite a further increase in MAP.     

维持性血液透析患者心率变异性对心源性死亡率的影响

目的评估心率变异性(heart rate variability,HRV)下降对终末期肾脏病维持性血液透析患者的临床意义及对心源性死亡率的影响。方法对64例维持性血液透析患者[年龄(58±15)岁,男性25例,透析时间(42±54)月]进行24h动态心电图描述并分析时域和频域HRV指标。结果参试患者与30例健康人群对照,HRV显著性减低。在2年随访期间中,共有13例患者死亡(20.3%);6例为心源性死亡、7例为非心源性死亡。Cox生存分析提示,在HRV检测指标中,窦性心搏间期标准差(SDNN)、超低频功率、RR间期心率变异比值(LF/HF)对于心源死亡有显著性指示意义。而对非心源死亡病例,HRV检测各指标均无显著性指示意义。结论 HRV指标水平降低,对于维持性血液透析患者的心源性死亡有显著性预测意义。     

Autonomic response to cardiac dysfunction in chronic heart failure: a risk predictor based on autonomic information flow

Background: Chronic heart failure (CHF) is associated with a complex dysfunction of cardiac, cardiovascular, autonomic, and other mechanisms. Autonomic information flow (AIF) characteristics calculated from heart rate patterns were recently found as promising predictors of outcome in several cardiovascular diseases.
Aim: To assess the prognostic value of AIF indices in CHF patients.
Methods: We analyzed 24-hour Holter recordings from 200 consecutive CHF patients in sinus rhythm and computed AIF over the shortest possible interval of an interbeat series, namely over one heart beat interval (BDnn), and over longer intervals (12.5–166.7 seconds, PDmVLF), which reflect slower heart rate modulations. End-point for survival analysis over three years (Cox model) was total cardiac death. A prognostic model was built (backward elimination) considering known clinical and functional risk factors, and the ability of AIF indices to add prognostic information to this model assessed.
Results: Out of candidate predictors, New York Heart Association class, left ventricular ejection fraction, peak VO_2, and systolic pressure were selected as the variables with the highest joint predictive value. When entered into this model, both BDnn and PDmVLF added prognostic information (HR (95%CI): 1.76 (1.00–3.09), P = 0.05, 1.73 (1.05–2.85), P = 0.031 respectively). High risk was associated with reduced fast AIF and increased slower AIF.
Conclusion: In CHF patients, AIF indices provide prognostic information independent of known risk factors.     

Immediate effects of the high-velocity low-amplitude thrust on the heart rate autonomic modulation of judo athletes

IntroductionThere is controversy about the repercussions of high speed-low amplitude thrust (HVLAT) manipulation in the thoracic region on the autonomic nervous system. Objective: To evaluate the immediate effects of the HVLAT in the high thoracic region on the heart rate autonomic modulation of judo athletes.MethodsIn the experimental study, thirty-eight healthy men divided into 2 groups (Judo athletes and non-athletes) having heart rate variability (HRV) collected beat-to-beat using a cardio-pacemater during all stages of the manipulation: i) rest, ii) time 1 (participant positioning), iii) time 2 (positioning of the participant together with the therapist), iv) HVLAT manipulation, v) post 5min, vi) post 10min and vii) post 15min HVLAT. Systolic blood pressure (SBP), diastolic blood pressure (DBP), breath frequency (BF), and HRV were also analyzed.ResultsA higher sympathetic modulation was observed with an increase in the standard deviation of successive normal R-R intervals (SDNN) and SD2 indices representing the total variability, however, there was no significant statistical difference in the root mean square of the mean squared differences (RMSSD), percentual of interval differences of successive NN intervals greater than 50 ms (pNN50), and SD1 variables, which represent the parasympathetic nervous system.ConclusionHVLAT manipulation was able to decrease HRV during manipulation, reflecting sympathetic hyperactivity. However, the return of the HRV indices to the baseline conditions in the first minutes of recovery in Judo athletes and non-athletes reflected the safety of the application of the manipulation in these conditions studied.