Peritoneal dialysis and neurological outcome in infants and small children

Although improved outcomes for children on peritoneal dialysis (PD) have been seen in recent years, the youngest patients continue to demonstrate inferior growth, more frequent infections, more neurological sequelae, and higher mortality compared to older children. Also, maintain-ing normal intravascular volume status, especially in anuric patients, has proven difficult. This study was designed to treat and monitor these youngest PD patients, which are relatively many due to the high prevalence of congenital nephrotic syndrome of the Finnish type (CNF, NPHS1) in Finland, with a strict protocol, to evaluate the results and to improve metabolic balance, growth, and development. A retrospective analysis of 23 children under two years of age at onset of PD, treated between 1995 and 2000, was performed to obtain a control population for our prospective PD study. Respectively, 21 patients less than two years of age at the beginning of PD were enrolled in prospective studies between 2001 and 2005. Medication for uremia and nutrition were care-fully adjusted during PD. Laboratory parameters and intravascular volume status were regu-larly analyzed. Growth was analyzed and compared with midparental height. In a prospective neurological study, the risk factors for development and the neurological development was determined. Brain images were surveyed. Hearing was tested. In a retrospective neurological study, the data of six NPHS1 patients with a congruent neurological syndrome was analyzed. All these patients had a serious dyskinetic cerebral palsy-like syndrome with muscular dysto-nia and athetosis (MDA). They also had a hearing defect. Metabolic control was mainly good in both PD patient groups. Hospitalization time shortened clearly. The peritonitis rate diminished. Hypertension was a common problem. Left ventricular hypertrophy decreased during the prospective study period. None of the patients in either PD group had pulmonary edema or dialysis-related seizures. Growth was good and catch-up growth was documented in most patients in both patient groups during PD. Mortality was low (5% in prospective and 9% in retrospective PD patients). In the prospective PD patient group 11 patients (52%) had some risk factor for their neuro-development originating from the predialysis period. The neurological problems, detected be-fore PD, did not worsen during PD and none of the patients developed new neurological com-plications during PD. Brain infarcts were detected in four (19%) and other ischemic lesions in three patients (14%). At the end of this study, 29% of the prospectively followed patients had a major impairment of their neurodevelopment and 43% only minor impairment. In the NPHS1+MDA patients, no clear explanation for the neurological syndrome was found. The brain MRI showed increased signal intensity in the globus pallidus area. Kernic-terus was contemplated to be causative in the hypoproteinemic newborns but it could not be proven. Mortality was as high as 67%. Our results for young PD patients were promising. Metabolic control was acceptable and growth was good. However, the children were significantly smaller when compared to their midparental height. Although many patients were found to have neurological impairment at the end of our follow-up period, PD was a safe treatment whereby the neurodevelopment did not worsen during PD.

Treatment of illicit opioid and γ-hydroxybutyrate overdose by Helsinki emergency medical services

Aims: To examine the characteristics, incidence, treatment and outcome of presumed opioid, γ-hydroxybutyrate (GHB) and γ-butyrolactone (GBL) overdoses involving users of illicit drugs in Helsinki. GHB/GBL were included in this study, despite not being opioids, due to the relative ease with which they can cause potentially fatal respiratory depression. The incidence and time interval of recurrent opioid toxicity after prehospital administration of naloxone, an opioid antagonist, was studied in presumed heroin overdose patients. Naloxone has been reported to have many adverse effects and the effects of naloxone administered during an opioid overdose on the cardiovascular system and catecholamine levels in piglets were studied. Materials and methods: Patients included in these published retrospective studies were from the following time periods: Study I: 1995-2002, II: 1997-2000, III: 1995-2000, V: 2006-2007. Presumed opioid overdose patients were examined in studies I, II and III. GHB/GBL overdoses among injecting drug users was examined in study V. Recurrent opioid toxicity after prehospital naloxone administration in heroin overdose patients was examined in study III. The effects of naloxone (80 μg/kg i.v.) on the cardiovascular system and catecholamine levels administered during morphine overdose (8mg/kg i.v.) and under propofol anesthesia with spontaneous breathing were studied in eight piglets (IV). In this thesis, previously unpublished data on the incidence of opioid overdose between 2001-2007 and comparison of the characteristics of buprenorphine and heroin overdose patients encountered in 1995-2005 are also included. Results: Helsinki Emergency Medical Service (EMS) ambulances were dispatched annually to 34,153- 45,118 calls from 1995 to 2007. Of them, 7-8% were coded as intoxications or overdoses. During this time, 436 patients were treated by the EMS for presumed opioid overdose. The peak incidence of opioid overdoses was in the year 2000 (113 cases), after which they declined to 6-26 cases annually. The annual incidence of buprenorphine related overdoses increased from 4 (4% of opioid overdoses) in the year 2000 to 8 (30% of opioid overdoses) in 2007. The annual number of GHB related overdose patients treated by Helsinki EMS increased from 21 to 73 between 2004-2007. There appeared to be a peak in the incidence of both GHB/GBL and opioid related overdoses on Saturdays. Characteristics of opioid overdose patients The median age of opioid overdose patients was 28 years (22;33, 25- and 75-percentiles), and 84% were male. Buprenorphine overdose patients had more polydrug, such as alcohol and/or benzodiazepines, use in comparison with heroin overdose patients, 70% versus 33%, respectively. Severe respiratory depression was reported less often with buprenorphine overdoses compared to heroin overdoses, in 67.0% versus 85.4%, respectively. Outcome of heroin overdose patients with cardiac arrest Ninety four patients suffered cardiac arrest due to acute drug poisoning/overdose and were thus considered for resuscitation. Resuscitation was attempted in 72 cases. Cardiac arrest was caused by heroin overdose for 19 patients of which three (16%) were discharged alive. Other agents also induced cardiac arrest in 53 patients, of which six (11%) were discharged alive. The arrest was either EMS witnessed or occurring after the emergency call for all survivors of heroin induced cardiac arrest. Characteristics of GHB/GBL overdose patients The records of 100 GHB/GBL related overdose patients from 2006-2007 were retrieved. The median age of GHB/GBL overdose patients encountered on weekend nights was 24 years (22;27, 25- and 75-percentiles) and 49% were male. Polydrug use was reported in 62-80% of the cases. Thirty nine patients were encountered on Friday-Saturday or Saturday-Sunday night between 11 pm-6 am. The remaining sixty one patients were outside this time frame. There was a statistically significant difference between these two groups in history of chronic injecting drug use (33% vs. 59%, respectively, p=0.012). Recurrent heroin toxicity after prehospital naloxone administration Study III included 145 presumed heroin overdose patients. After prehospital care, 84 patients refused further care and were not transported to an Emergency Department (ED). Seventy one (85%) of them were administered naloxone by the EMS. During a 12-h follow up period, none of these patients developed severe recurrent opioid toxicity. The remaining 61 patients were transported to an ED. Prior to transportation, 52 (85%) patients were administered naloxone by the EMS. Fifteen of them were administered naloxone also in the ED and recurrent opioid toxicity was evident either on arrival at the ED or shortly thereafter. Prehospital naloxone was administered either intravenously, intramuscularly (i.m.) or subcutaneously (s.c.). There was a tendency for more frequent recurrent heroin toxicity among the patients with only intravenous administration of prehospital naloxone (13/36) compared with the patients with intramuscular or subcutaneous prehospital naloxone (2/16), p=0.106. The effects of naloxone on the cardiovascular system and catecholamine levels in piglets The administration of morphine to piglets resulted in an obvious respiratory depression, which was reversed by naloxone. Two severely hypoxemic piglets developed cardiac arrest after naloxone administration. In the other six animals, the administration of naloxone did not provoke arrhythmias, cardiac ischemia or visible evidence of pulmonary edema. There was a statistically significant (p=0.012) increase in norepinephrine levels after morphine administration and before naloxone administration: from 1.9 (1.3-2.3) ng/ml at baseline, to 31.7 (8.3-83.0) ng/ml (median, 25 and 75 percentiles parentheses) after morphine administration. After the administration of naloxone, the catecholamine levels continued to increase in only one of the animals. Conclusions: The incidence of buprenorphine related overdoses increased during the study period, but was still lower in comparison to those involving heroin. Injecting drug users have also started to use GHB/GBL. While recreational drug users use GHB/GBL during weekend nights, a GHB/GBL overdose patient encounter during weekdays has a more probable history of injecting drug use. Patients with cardiac arrest after heroin overdose have a poor prognosis. It appears to be safe to leave heroin overdose patients on scene after prehospital treatment with naloxone. Although no statistically significant difference was observed, it seems prudent to administer part of the total naloxone dose s.c. or i.m. to reduce the risk of recurrent respiratory depression. If transported to an ED, an observation period of one to two hours after the last naloxone dose seems adequate. The treating physician must be vigilant, however, due to the high prevalence of polydrug use and high morbidity after non fatal heroin overdose. Furthermore, care should be taken regarding possible chronic disorders and drug rehabilitation should be addressed. In the experimental animal study, two animals developed cardiac arrest after receiving naloxone while in hypoxemia and bradycardia. Further studies are required to assess the effect of naloxone during opioid-induced hypercapnia and hypoxemia in animals addicted to opioids.

New Concepts for PVC Detection

A new scheme is proposed for the detection of premature ventricular beats, which is a vital function in rhythm monitoring of cardiac patients. A transformation based on the first difference of the digitized electrocardiogram (ECG) signal is developed for the detection and delineation of QRS complexes. The method for classifying the abnormal complexes from the normal ones is based on the concepts of minimum phase and signal length. The parameters of a linear discriminant function obtained from a training feature vector set are used to classify the complexes. Results of application of the scheme to ECG of two arrhythmia patients are presented.

Myoblast Sheet Transplantation for Treatment of Heart Failure after Myocardial Infarction

Heart failure is a common, severe, and progressive condition associated with high mortality and morbidity. Because of population-aging in the coming decades, heart failure is estimated to reach epidemic proportions. Current medical and surgical treatments have reduced mortality, but the prognosis for patients has remained poor. Transplantation of skeletal myoblasts has raised hope of regenerating the failing heart and compensating for lost cardiac contractile tissue. In the present work, we studied epicardial transplantation of tissue-engineered myoblast sheets for treatment of heart failure. We employed a rat model of myocardial infarction-induced acute and chronic heart failure by left anterior descending coronary artery ligation. We then transplanted myoblast sheets genetically modified to resist cell death after transplantation by expressing antiapoptotic gene bcl2. In addition, we evaluated the regenerative capacity of myoblast sheets expressing the cardioprotective cytokine hepatocyte growth factor in a rat chronic heart failure model. Furthermore, we utilized in vitro cardiomyocyte and endothelial cell culture models as well as microarray gene expression analysis to elucidate molecular mechanisms mediating the therapeutic effects of myoblast sheet transplantation. Our results demonstrate that Bcl2-expression prolonged myoblast sheet survival in rat hearts after transplantation and induced secretion of cardioprotective, proangiogenic cytokines. After acute myocardial infarction, these sheets attenuated left ventricular dysfunction and myocardial damage, and they induced therapeutic angiogenesis. In the chronic heart failure model, inhibition of graft apoptosis by Bcl-2 improved cardiac function, supported survival of cardiomyocytes in the infarcted area, and induced angiogenesis in a vascular endothelial growth factor receptor 1- and 2-dependent mechanism. Hepatocyte growth factor-secreting myoblast sheets further enhanced the angiogenic efficacy of myoblast sheet therapy. Moreover, myoblast-secreted paracrine factors protected cardiomyocytes against oxidative stress in an epidermal growth factor receptor- and c-Met dependent manner. This protection was associated with induction of antioxidative genes and activation of the unfolded protein response. Our results provide evidence that inhibiting myoblast sheet apoptosis can enhance the sheets efficacy for treating heart failure after acute and chronic myocardial infarction. Furthermore, we show that myoblast sheets can serve as vehicles for delivery of growth factors, and induce therapeutic angiogenesis in the chronically ischemic heart. Finally, myoblasts induce, in a paracine manner, a cardiomyocyte-protective response against oxidative stress. Our study elucidates novel mechanisms of myoblast transplantation therapy, and suggests effective means to improve this therapy for the benefit of the heart failure patient.

Sydämen hypertrofian ja kroonisen vajaatoiminnan farmakologinen hoito

Sydämen krooninen vajaatoiminta on merkittävä maailmanlaajuinen ongelma. Se on erilaisten sydän- ja verisuonisairauksien aiheuttama monimuotoinen oireyhtymä. Sydämen vasemman kammion hypertrofia eli sydämen seinämien paksuuntuminen on yksi keskeinen tekijä, joka voi olla sydämen vajaatoiminnan taustalla. Kohonnut verenpaine on yleisin syy, joka johtaa sydänlihaksen paksuuntumiseen. Tämä johtaa sydämen pumppaustoiminnan häiriintymiseen, erilaisten neurohormonaalisten mekanismien aktivaatioon ja edelleen sydämen vajaatoimintaan. Sydämen vajaatoiminnan neurohormonaalisista mekanismeista tärkeimmät ovat reniini-angiotensiini-aldosteroni-järjestelmän ja sympaattisen hermoston aktivaatio, sydämen rakenteiden uudelleenmuovautuminen, sydänlihassolujen apoptoosi ja systeeminen tulehdustila. Sydämen hypertrofiaa ja sen syntymistä pyritään estämään kohonneen verenpaineen lääkehoidolla. Reniini-angiotensiini-aldosteronijärjestelmällä on keskeinen merkitys sydämen vajaatoiminnassa. Sydämen vajaatoiminnan ennusteeseen vaikuttavista lääkeaineista angiotensiinikonvertasin estäjät (ACEestäjät) ovat säilyttäneet johtoasemansa jo vuosikymmenten ajan. Angiotensiinireseptoreiden salpaajien (AT1-salpaajien) odotettiin syrjäyttävän ACE-estäjät sydämen vajaatoiminnan hoidossa, mutta toistaiseksi niitä pidetään vain vaihtoehtoisina lääkkeinä. Sympaattisen hermoston aktivaatiota vähentävät β-salpaajat ovat vakiinnuttaneet asemansa toiseksi tärkeimpänä lääkeryhmänä. Diureetit ovat paljon käytetty lääkeaineryhmä sydämen vajaatoiminnan hoidossa, mutta niistä ainoastaan aldosteroniantagonisteilla on tutkitusti ennustetta parantavaa vaikutusta. Kroonisen vajaatoiminnan hoidossa käytetään edelleen myös digoksiinia. Tulevaisuudessa sydämen vajaatoiminnan ennusteeseen vaikuttavia lääkeaineita voivat olla reniinin estäjät, neutraaliendopeptidaasin estäjät, vasopressiinin antagonistit tai inflammatroisiin sytokiineihin vaikuttavat molekyylit. Erikoistyön kokeellisessa osiossa tarkoituksena oli tutkia sydämen hypertrofian kehittymistä vatsa-aortta kuristetuilla rotilla ja kalsiumherkistäjä levosimendaanin sekä AT1-salpaaja valsartaanin vaikutuksia hypertrofian kehittymiseen. Kokeellisessa osiossa arvioitiin myös sydämen hypertrofian ja vajaatoiminnan jyrsijämallina käytetyn vatsa-aortan kuristuksen (koarktaation) toimivuutta ja vaikutuksia ultraäänen avulla määritettyihin kardiovaskulaarisiin parametreihin. Vatsa-aortta kuristettiin munuaisvaltimoiden yläpuolelta. Kuristus saa aikaan verenpaineen kohoamisen ja sydämen työtaakan lisääntymisen. Pitkittyessään tila johtaa sydänlihaksen hypertrofiaan ja vajaatoimintaan. 64 eläintä jaettiin ryhmiin, siten että jokaiseen ryhmään tuli kahdeksan eläintä. Ryhmistä kolmelle annettiin lääkeaineena levosimendaania kolmella eri päiväannoksella (0,01 mg/kg; 0,10 mg/kg; 1,00 mg/kg) ja kolmelle valsartaania kolmella eri päiväannoksella (0,10 mg/kg; 1,00 mg/kg; 10,00 mg/kg) juomaveden mukana. Lääkitys aloitettiin leikkauksen jälkeen ja jatkettiin kahdeksan viikon ajan. Kardiovaskulaariset parametrit, kuten isovolumetrinen relaksaatioaika (IVRT), vasemman kammion läpimitta systolessa ja diastolessa sekä seinämäpaksuudet, ejektiofraktio (EF), supistuvuusosuus (FS), minuuttitilavuus (CO) ja iskutilavuus (SV) määritettiin kahdeksan viikon kuluttua leikkauksesta ultraäänitutkimuksen avulla. Lisäksi määritettiin eläinten sydämen paino suhteessa ruumiin painoon. Tuloksia verrattiin ilman lääkehoitoa olleeseen koarktaatioryhmään. Eläinmallin toimivuutta arvioitiin vertaamalla koarktaatioryhmän tuloksia sham-operoidun ryhmän tuloksiin. Levosimendaanilla havaittiin työssä sydämen systolista toimintaa parantava vaikutus. Tämä näkyi tendenssinä parantaa ejektiofraktioita ja vasemman kammion supistuvuusosuuksia. Sydämen diastoliseen toimintaan ei kummallakaan lääkeaineella ollut merkittävää vaikutusta. Diastolista toimintaa arvioitiin isovolumetrisen relaksaatioajan muutoksilla. Sydämen hypertrofian kehittymiseen ei kummallakaan lääkeaineella ollut merkittävää vaikutusta. Eläinmallin todettiin mallintavan hyvin sydämen hypetrofiaa ihmisellä, mutta ei niinkään sydämen vajaatoimintaa.

A Fluidic Drive System for Intra-Aortic Balloon Heart Assist Device

Intra-aortic balloon pumping is a counter pulsation technique for temporary circulatory assistance in cardiogenic shock and other low cardiac output conditions. Conventional systems use a balloon at the end of a catheter driven by a solenoid valve, controlled by patient's ECG or ventricular pressure signal. This results in time delay introducted by solenoid spool inertia, gas inertia, and hysteresis effects of the solenoid. Fluidics, because of their non-moving part operation and high switching speeds, minimizes the inertial effects while contributing high reliability. This communication describes a fluidic system developed for driving the balloon accepting electric control signals.

Nonequilibrium arrhythmic states and transitions in a mathematical model for diffuse fibrosis in human cardiac tissue

We present a comprehensive numerical study of spiral-and scroll-wave dynamics in a state-of-the-art mathematical model for human ventricular tissue with fiber rotation, transmural heterogeneity, myocytes, and fibroblasts. Our mathematical model introduces fibroblasts randomly, to mimic diffuse fibrosis, in the ten Tusscher-Noble-Noble-Panfilov (TNNP) model for human ventricular tissue; the passive fibroblasts in our model do not exhibit an action potential in the absence of coupling with myocytes; and we allow for a coupling between nearby myocytes and fibroblasts. Our study of a single myocyte-fibroblast (MF) composite, with a single myocyte coupled to N-f fibroblasts via a gap-junctional conductance G(gap), reveals five qualitatively different responses for this composite. Our investigations of two-dimensional domains with a random distribution of fibroblasts in a myocyte background reveal that, as the percentage P-f of fibroblasts increases, the conduction velocity of a plane wave decreases until there is conduction failure. If we consider spiral-wave dynamics in such a medium we find, in two dimensions, a variety of nonequilibrium states, temporally periodic, quasiperiodic, chaotic, and quiescent, and an intricate sequence of transitions between them; we also study the analogous sequence of transitions for three-dimensional scroll waves in a three-dimensional version of our mathematical model that includes both fiber rotation and transmural heterogeneity. We thus elucidate random-fibrosis-induced nonequilibrium transitions, which lead to conduction block for spiral waves in two dimensions and scroll waves in three dimensions. We explore possible experimental implications of our mathematical and numerical studies for plane-, spiral-, and scroll-wave dynamics in cardiac tissue with fibrosis.

Turbulent electrical activity at sharp-edged inexcitable obstacles in a model for human cardiac tissue

Wave propagation around various geometric expansions, structures, and obstacles in cardiac tissue may result in the formation of unidirectional block of wave propagation and the onset of reentrant arrhythmias in the heart. Therefore, we investigated the conditions under which reentrant spiral waves can be generated by high-frequency stimulation at sharp-edged obstacles in the ten Tusscher-Noble-Noble-Panfilov (TNNP) ionic model for human cardiac tissue. We show that, in a large range of parameters that account for the conductance of major inward and outward ionic currents of the model fast inward Na+ current (INa), L-type slow inward Ca2+ current (I-CaL), slow delayed-rectifier current (I-Ks), rapid delayed-rectifier current (I-Kr), inward rectifier K+ current (I-K1)], the critical period necessary for spiral formation is close to the period of a spiral wave rotating in the same tissue. We also show that there is a minimal size of the obstacle for which formation of spirals is possible; this size is similar to 2.5 cm and decreases with a decrease in the excitability of cardiac tissue. We show that other factors, such as the obstacle thickness and direction of wave propagation in relation to the obstacle, are of secondary importance and affect the conditions for spiral wave initiation only slightly. We also perform studies for obstacle shapes derived from experimental measurements of infarction scars and show that the formation of spiral waves there is facilitated by tissue remodeling around it. Overall, we demonstrate that the formation of reentrant sources around inexcitable obstacles is a potential mechanism for the onset of cardiac arrhythmias in the presence of a fast heart rate.

A Computational Study of the Factors Influencing the PVC-Triggering Ability of a Cluster of Early Afterdepolarization-Capable Myocytes

Premature ventricular complexes (PVCs), which are abnormal impulse propagations in cardiac tissue, can develop because of various reasons including early afterdepolarizations (EADs). We show how a cluster of EAD-generating cells (EAD clump) can lead to PVCs in a model of cardiac tissue, and also investigate the factors that assist such clumps in triggering PVCs. In particular, we study, through computer simulations, the effects of the following factors on the PVC-triggering ability of an EAD clump: (1) the repolarization reserve (RR) of the EAD cells; (2) the size of the EAD clump; (3) the coupling strength between the EAD cells in the clump; and (4) the presence of fibroblasts in the EAD clump. We find that, although a low value of RR is necessary to generate EADs and hence PVCs, a very low value of RR leads to low-amplitude EAD oscillations that decay with time and do not lead to PVCs. We demonstrate that a certain threshold size of the EAD clump, or a reduction in the coupling strength between the EAD cells, in the clump, is required to trigger PVCs. We illustrate how randomly distributed inexcitable obstacles, which we use to model collagen deposits, affect PVC-triggering by an EAD clump. We show that the gap-junctional coupling of fibroblasts with myocytes can either assist or impede the PVC-triggering ability of an EAD clump, depending on the resting membrane potential of the fibroblasts and the coupling strength between the myocyte and fibroblasts. We also find that the triggering of PVCs by an EAD clump depends sensitively on factors like the pacing cycle length and the distribution pattern of the fibroblasts.

Mechanisms Responsible for the Trophic Effect of Beta-Adrenoceptors on the I-to Current Density in Type 1 Diabetic Rat Cardiomyocytes

Background/Aims: In diabetic ventricular myocytes, transient outward potassium current (I-to) amplitude is severely reduced because of the impaired catecholamine release that characterizes diabetic autonomic neuropathy. Sympathetic nervous system exhibits a trophic effect on I-to since incubation of myocytes with noradrenaline restores current amplitude via beta-adrenoceptor (beta AR) stimulation. Here, we investigate the intracellular signalling pathway though which incubation of diabetic cardiomyocytes with the beta AR agonist isoproterenol recovers I-to amplitude to normal values. Methods: Experiments were performed in ventricular myocytes isolated from streptozotocin-diabetic rats. I-to current was recorded by using the patch-clamp technique. Kv4 channel expression was determined by immunofluorescence. Protein-protein interaction was determined by coimmunoprecipitation. Results: Stimulation of beta AR activates first a G alpha s protein, adenylyl cyclase and Protein Kinase A. PKA-phosphorylated receptor then switches to the G alpha i protein. This leads to the activation of the beta AR-Kinase-1 and further receptor phosphorylation and arrestin dependent internalization. The internalized receptor-arrestin complex recruits and activates cSrc and the MAPK cascade, where Ras, c-Raf1 and finally ERK1/2 mediate the increase in Kv4.2 and Kv4.3 protein abundance in the plasma membrane. Conclusion: beta(2)AR stimulation activates a G alpha s and G alpha i protein dependent pathway where the ERK1/2 modulates the Ito current amplitude and the density of the Kv4.2 and Kv4.2 channels in the plasma membrane upon sympathetic stimulation in diabetic heart.

Role of G protein coupled inwardly rectifier K+ channels (GIRK) on the neurobiology depression

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Rhythm Analysis during Cardiopulmonary Resuscitation: Past, Present, and Future

Survival from out-of-hospital cardiac arrest depends largely on two factors: early cardiopulmonary resuscitation (CPR) and early defibrillation. CPR must be interrupted for a reliable automated rhythm analysis because chest compressions induce artifacts in the ECG. Unfortunately, interrupting CPR adversely affects survival. In the last twenty years, research has been focused on designing methods for analysis of ECG during chest compressions. Most approaches are based either on adaptive filters to remove the CPR artifact or on robust algorithms which directly diagnose the corrupted ECG. In general, all the methods report low specificity values when tested on short ECG segments, but how to evaluate the real impact on CPR delivery of continuous rhythm analysis during CPR is still unknown. Recently, researchers have proposed a new methodology to measure this impact. Moreover, new strategies for fast rhythm analysis during ventilation pauses or high-specificity algorithms have been reported. Our objective is to present a thorough review of the field as the starting point for these late developments and to underline the open questions and future lines of research to be explored in the following years.

Flexible microimplants for in vivo sensing

The work in this thesis develops two types of microimplants for the application of cardiovascular in vivo biomedical sensing, one for short-term diagnosis and the other for long-term monitoring.

Despite advances in diagnosis and therapy, atherosclerotic cardiovascular disease remains the leading cause of morbidity and mortality in the Western world. Predicting metabolically active atherosclerotic plaques has remained an unmet clinical need. A stretchable impedance sensor manifested as a pair of quasi-concentric microelectrodes was developed to detect unstable intravascular. By integrating the impedance sensor with a cardiac catheter, high-resolution Electrochemical Impedance Spectroscopy (EIS) measurements can be conducted during cardiac catheterization. An inflatable silicone balloon is added to the sensor to secure a well-controlled contact with the plaque under test in vivo. By deploying the device to the explants of NZW rabbit aorta and live animals, distinct EIS measurements were observed for unstable atherosclerotic plaques that harbored active lipids and inflammatory cells.

On the other hand, zebrafish (Danio rerio) is an emerging genetic model for heart regenerative medicine. In humans, myocardial infarction results in the irreversible loss of cardiomyocytes. Zebrafish hearts can fully regenerate after two months with 20% ventricular resection. Long-term electrocardiogram (ECG) recording can characterize the heart regeneration in a functional dimension. A flexible microelectrode membrane was developed to be percutaneously implanted onto a zebrafish heart and record epicardial ECG signals from specific regions on it. Region-specific aberrant cardiac signals were obtained from injured and regenerated hearts. Following that, in order to achieve continuous and wireless recording from non-sedated and non-restricted small animal models, a wireless ECG recording system was designed for the microelectrode membrane, prototyped on a printed circuit board and demonstrated on a one-day-old neonatal mouse. Furthermore, a flexible and compact parylene C printed circuit membrane was used as the integration platform for the wireless ECG recording electronics. A substantially miniature wireless ECG recording system was achieved.

Dieta hiperlipídica com ou sem adição de sal modula diferentemente a produção de peptídeo natriurético atrial e a expressão de renina em camundongos

Estudo dos efeitos de uma dieta rica em sal e / ou gordura saturada em grânulos de peptídeo natriurético atrial (ANP), hipertensão, expressão da renina e ultraestrutura cardíaca em camundongos C57Bl / 6. Camundongos machos adultos jovens foram separados em quatro grupos (n = 12) e alimentados com uma das seguintes dietas por 9 semanas: dieta padrão para roedores (Grupo P), dieta hiperlipídica (Grupo HL), dieta hipersódica (Grupo HS) e dieta hiperlipídica e hipersódica simultaneamente (HL-HS). Foram examinados: alterações no ANP sérico, ultra-estrutura dos cardiomiócitos produtores de ANP, estrutura do ventrículo esquerdo, pressão arterial sanguínea, expressão da renina no rim, taxa de filtração glomerular (TFG), eficiência alimentar, parâmetros lipídicos e glicídicos. Os animais alimentados com dieta hiperlipídica mostraram um pequeno aumento na produção de ANP, discreta hipertrofia ventricular esquerda, aumento da eficiência alimentar, dislipidemia e hiperglicemia. Animais alimentados com dieta hipersódica tiveram um grande aumento na produção de grânulos de ANP e correspondente elevação do seu nível sérico, hipertrofia ventricular esquerda, hipertensão arterial, diminuição dos níveis de renina e aumento da TFG. A combinação das duas dietas (HL-HS) teve um efeito aditivo. A ingestão de uma dieta com alto teor de sal e lipídeos induz alterações ultraestruturais dos cardiomiócitos, aumento da produção de ANP e elevação de seu nível sérico e reduz a quantidade de renina no rim.

Variabilidade ventilatória durante exercício dinâmico em indivíduos saudáveis e com insuficiência cardíaca

A presença de ventilação periódica durante o exercício confere pior prognóstico a pacientes com insuficiência cardíaca. Existem divergências quanto aos critérios para identificação deste fenômeno. Além disso, a interpretação dicotômica (presença ou ausência) quanto a este fenômeno dificulta a estratificação de risco mais detalhada dos pacientes com insuficiência cardíaca. Desta forma, esta tese avalia a utilização de técnicas estabelecidas para análise de variabilidade de sinais para quantificar as oscilações ventilatórias que ocorrem durante o teste cardiopulmonar de exercício, em indivíduos saudáveis, atletas e com insuficiência cardíaca. Um protocolo mais curto para realização de teste cardiopulmonar de exercício em cicloergômetro de braço foi proposto e validado. Tal protocolo foi utilizado em estudo posterior, onde se comprovou que, apesar dos tempos respiratórios não serem influenciados pelo tipo de exercício realizado, a variabilidade ventilatória é maior durante a realização de exercício dinâmico com membros superiores do que com membros inferiores. A capacidade aeróbica de indivíduos sadios também influencia a variabilidade ventilatória durante o teste cardiopulmonar de exercício. Isto foi comprovado pela menor variabilidade ventilatória no domínio do tempo em atletas do que sedentários durante exercício. A análise destes voluntários com o método da análise dos componentes principais revelou que em atletas a variabilidade do volume corrente é a principal responsável pela variabilidade da ventilação-minuto durante o exercício, ao passo que em sedentários a variabilidade da freqüência respiratória apresenta-se como principal responsável por tais variações. Em estudo randomizado e controlado comprovamos que, mesmo indivíduos sadios apresentam redução da variabilidade ventilatória ao exercício após 12 semanas de treinamento físico. Comprovamos que a reabilitação cardíaca reverteu a ocorrência de ventilação periódica em um paciente com insuficiência cardíaca e, finalmente, encontramos que a variabilidade ventilatória correlaciona-se inversamente com a fração de ejeção ventricular esquerda em pacientes com insuficiência cardíaca. Estudos futuros deverão analisar o poder prognóstico da variabilidade ventilatória nestes pacientes.