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\r\n\tThe objective of the book is to consolidate and compile the articles representing the modern trends in research of Annelida. The multidimensional aspects of Annelida contributed by the scientists of different disciplines would be the major attraction of this publication. This book will provide a rich source of biological information for the students, teachers and scientists working in this domain. Leading cell biologists working in the area of Invertebrate biology are also expected to contribute a valuable chapter in this book.
Malaria is spreading from old Plasmodium colonized territories to other zones of the earth where this lethal disease did not exist before covering about 45% of the planet. Over decades an important number of public health trials for malaria eradication and control have been conducted with a limited success. Malaria is caused by Plasmodium spp. to a susceptible human being and is transmitted by the Anopheles female mosquito bite and is responsible of 660,000 deaths and around 219 million new cases annually (a range of 154–289 million) especially in children younger than 5 years of age and pregnant women inhabitants of endemic and high transmission areas [1–3].
\nA number of difficulties inherent to many causes among the pathogen resistance to antimalarials, poor coverage of public health programs and natural human host genetic restrictions make the finding of an effective malaria vaccine be an urgent need.
\nMalaria vaccine development has constituted a big challenge for researchers, up-to-date about 236 vaccine candidate prototypes are being tested. Approaches based on strategies such as immunization with irradiated sporozoites of Plasmodium spp., as well as DNA-based immunogens besides recombinantly expressed antigens such as RTS,S formulated in different vehicles and strong adjuvant systems and prototype delivery systems such as virosomes besides to the most promising strategy constituted by synthetic peptides representing subunit multistage immunogens formulated in human allowed adjuvants represent the main attempts for immuno-prophylaxis [2].
\nPlasmodium spp. express a number of antigens, more than 100 in its different life cycle stages and most of them have been regarded as vaccine targets such as the so-named merozoite surface antigens 1–10 (MSP1–MSP10), erythrocyte binding antigens EBA-140 and EBA-175, the ring-infected erythrocyte surface antigen (RESA-155), the apical membrane antigen AMA-1 among many others from the merozoite stage including a number of organelle’s proteins. Besides the circumsporozoite surface protein (CSP), sporozoite threonine and asparagine-rich protein (STARP), the sporozoite and liver stage antigen (SALSA), the liver stage antigen (LSA) are some representative antigens of the sporozoite stage and the classical Pfs48/45, GSA and Pbs25/28 from gametocytes have been regarded as the targets for transmission blocking vaccines [4].
\nNatural immunity to malaria is related to hemoglobin structure, some disorders such as thalassemia confer resistance to Plasmodium falciparum while Duffy negative RBC constitutes the mechanisms associated to malaria resistance to Plasmodium vivax. Immune response against a natural malaria infection is nonspecific and has a weak effect on protection. Innate immunity mediated by NK and non-related auto antibody B-cells as well as the INF-gamma response to infected red blood cells act as a primary line of defense against Plasmodium infection. In the adaptative immunity step CD4+, dendritic cells, macrophages, gamma delta T cells and NKT cells are able to detect the parasite and participate in the immune defense. Besides natural immunity to this disease, an effective malaria vaccine can be proposed for a strong stimulation of antibody B-cells. However, at is has been demonstrated that most Plasmodium native-derived sequences are proven to be poorly immunogenic and non-protection inducers against malaria. In order to understand this problem, Patarroyo have established a strategy based on selection of non-polymorphic regions of selected antigens and a subsequent rational mutation of those residues belonging to red blood cells and hepatic cells binding motifs allow modified active antigens [4], however, most clinical trials worldwide which have been performed with the above mentioned malaria vaccine candidates have failed to achieve significant protection levels, evidencing intrinsic difficulties for developing a potent fully protective vaccine formulation. Perhaps pathogens including Plasmodium spp. have evolved complex mechanisms to recognize, block and destroy natural-presented antigens as vaccines as well as others related to antigen structure modulation.
\nOur group has introduced in this pursuit some non-natural elements to be incorporated into synthetic antigens with the aim of governing both antigen presentation as well as specific B-cells for functional neutralizing antibody stimulation. Some of these non-natural elements included capture sequences for stimulating antigen degradation and others for the peptide-bond structure modulation. Peptide-bond isosteres included reversal configuration thereof, urea motifs and reduced amide as peptide-bond surrogates all constituting a novel immunogen family herein named as immuno-mimetics.
\nOnce strategically incorporated into selected antigens, produced peptide-bond surrogates overcome non-desirable properties of native non-modified antigens such as cytotoxicity and hemolytic profiles, besides prolonging these new molecules half-life and a remarkably strong immuno-stimulating activity that can be associated to the newly introduced freedom degrees to the 3D structure of immuno-mimetics.
\nAlso, we have consolidated the female BALB/c animal model for malaria vaccine candidate testing based on controlled challenging performed to immunized animals with two rodent malaria strains, being those Plasmodium berghei ANKA and Plasmodium yoelii-17XL. Additionally, passive transferring antibodies into infected animals have proven to be efficient for malaria disease control and parasite clearance.
\nIn 2015, time for fulfillment of the millennium development goals (MDGs) was getting closer to the end, and a consequent protocol comprising 17 sustainable development goals (SDGs) constitute the next step. In its annual report, World Health Organization (WHO) analyzed 15 years of advances of those proposed MDG and evaluated the next challenges for the coming years.
\nAs reported in world health statistics 2015 issued by the WHO [1], undernutrition was the main cause of mortality in an assessed 45% of all deaths of children under 5 years of age. In the 1990–2013 period, the estimate of underweight children in third-world countries decreased from 28 to 17%, and a sustainable decreasing rate to 16% was expected for the end of 2015. In spite of those proposed efforts for achievement of MDG, these numbers are not still sufficient to the goals. The proportion of underweight children declined globally from 25% in 1990 to 15% in 2013.
\nWorryingly, poverty is strongly associated with public health especially to problems related to high transmission of infectious diseases. As observed in Figure 1A, among the main causes of deaths among children under 5 years (in neonatal and post-neonatal ages), between 2000 and 2013 are responsibility of infectious diseases, pneumonia, malaria, HIV/AIDS, measles, diarrhea and sepsis are the main reasons of mortality accounting 13 and 35%, respectively. Malaria represents 7% of children mortality mainly in the post-neonatal period between 1 and 59 months of age.
\nHealth statistics and world climate. (A) Causes of deaths among children under 5 years of age. (B) Top 10 countries with largest share of the global extreme poverty. (C) Main causes of child mortality due to transmissible diseases. 5.9 million children under age five died in 2015, nearly 16,000 every day. (D) Climate changes and greenhouse effect. Global average surface temperature changes under two scenarios for considering the global greenhouse gas emissions between years 1950 and 2100. RCP for representative concentration pathway. This figure has been adapted from information provided by WHO [1–3].
In the last year, 836 million of the world population lived on less than US$1.25 daily in comparison with 1.9 billion in 1990. In those the so-named poor countries, 14% of the people lived on less than US$1.25 daily in the same year, regarding the 47% in 1990. Getting closer to an amount of US$2 daily has been difficult at higher poverty levels.
\nThe most inhabited counties of the world such as People’s Republic of China and India have been crucial for world reduction in poverty (indeed India remains the earth’s country having most extreme poverty; Figure 1B) such reduction can be associated to growth of central economic sectors and labors. Other factors such as income transferring, remittances and evolving new demographic profiles have had a lesser impact. However, those efforts have not been enough since one of each seven people in poor countries live on less than US$1.25 daily. In the sub-Saharan countries, more than 40% people are living in extreme poverty in 2015. In the countries having middle-incomes, the 73% of the Earth’s poverty is found [3].
\nFigure 1B displays the top 10 countries with largest share of the global extreme poor, accordingly with WHO classifications, these countries are inhabited by people living on less than US$1.25 per day. Therefore, poverty levels show India 30%, Latin America 28%, China 8% and dramatically 20% represents African countries (Nigeria, Democratic Republic of the Congo, Ethiopia, United Republic of Tanzania, among others). Child mortality was 5.9 million children under age five which died in 2015, nearly 16,000 per day, mainly caused by infectious diseases whose distribution can be observed in Figure 1C. Main causes of child death are due to measles, malaria, diarrhea, HIV/AIDS, meningitis/encephalitis, tetanus and sepsis and other neonatal infections besides prematurity among other causes [1–3].
\nThe sustainable development goals (SDGs) also contain ambitious targets for child mortality, with SDG 3.2 seeking to end preventable deaths of newborns and children under five. Those have included local aims for reducing the under-five mortality rates (U5MR) around to 25 deaths per 1000 live births as well as the neonatal mortality rate (NMR) to lower than 12 per 1000 live births, in comparison with a world’s U5MR rate of 43 per 1000 live births in the last year, representing 5.9 million deaths of children under 5 years and a NMR rate of 19 per 1000 live births, representing 2.7 million deaths in the first month of life. Main causes of newborn mortality during the last year were prematurity, birth-related complications and neonatal sepsis, while those post-neonatal causes of death were associated to pneumonia, diarrhea, injuries and malaria. Specifically, the so-called Target 4.2 in the document, which encourage for assuring that most children have access to good quality development, heath assistance and care, and basic education join to reducing child mortality while improving a better living quality for childhood in most poor countries [3].
\nOn the other hand, Figure 1D displays climate changes and greenhouse effect on earth for a period between 1950 projected to the wear 2100. As described, global average surface temperature change is estimated under two scenarios for turning around global greenhouse gas emissions [1].
\nThe global climate warming is a reality. The average data for the Earth’s surface temperature showed a 0.85°C increasing (0.65–1.06) for the 1880–2012 period. Data show that the Earth’s north hemisphere had the warmest period from 1983 to 2013, being the highest regarding the last 1400 years. Without any doubt, most causes for this fact can be associated to human activities. Mathematical and predictive algorithms for global warming-cooling allow establishing precise predictions on climate changes over long-time periods, these have included factors such as volcanic activity and gas emissions to the atmosphere. The Intergovernmental Panel on Climate Change’s (IPCC) for temperature changing prediction have considered a number of factors and possibilities for future greenhouse gas emissions, which have been termed as representative concentration pathways (RCP). This ranges from RPC 2.6 which considers that global greenhouse gas emissions will reach a highest value between 2010 and 2020, then it significantly decrease after 2020, to RCP 8.5, in which greenhouse gas emissions will continue to increase during the present century. Middle-range positions consider that RCP 4.5 and 6.0 would reach the highest emission values in 2040 and 2080 in consequence [1].
\nWorld’s predictive temperature changes for 2015–2016 period regarding those recorded between 1986 and 2005 are estimated to vary between 0.3 and 0.7°C. Similarly, increasing temperature ranges for the 2081–2100 period regarding the recorded changes between 1986 and 2005 has been estimated to be 0.3–1.7°C (RCP 2.6) to 2.6–4.8°C (RCP 8.5) (Figure 1D). In consequence, the Arctic region’s warming rate will increase faster than the world’s mean, and that for the land’s rate will be higher than the mean for the ocean. Assessed RPCs led to estimate that sea level will growth from 0.26 to 0.82 m by the final of the current age. Earth’s surface warming and climate variations will have a deep impact on human living, health and welfare, since obtaining drinking water and the possibility of cultivating the necessary quantities of agricultural products and all resources required for the future world’s larger population will be compromised.
\nMalaria is a global disease responsibly of high levels of morbidity and mortality especially in developing countries whose inhabitant populations suffer the consequences of the disease besides the economic impact on these populations. At the beginning of the new millennium, a global strategy for controlling malaria by establishing a global founding for fighting three high impact diseases, i.e., AIDS, tuberculosis and malaria have been proposed by the World Health Organization (WHO) [5]. The 2015 world malaria report from WHO account data from 79 countries affected by this disease reflecting a slight improvement in controlling the disease impact but the problem still remains for a solution. In 2013, diagnosis tests were expanded to most malaria affecting countries and huge steps towards vector control were also conducted. In 2013, the use of insecticides impregnated mosquito nets were promoted and so the amount of populations protected against malaria were increased, thus mortality due to malaria was reduced to 47% between the years 2000 and 2013. However, endemic areas are still far away from reaching a total coverage for malaria control and available founding is each time decreased for managing this important problem. An estimated 278 million people in Africa live in households without a single insecticide mosquito net and 15 million pregnant women have no access to a preventive treatment for malaria. In addition, other diseases affecting these populations alter the development of related campaigns is the case of Ebola whose recent outbreak have conducted to a decreasing in health assistance in those affected zones.
\nIn the last five years, it is estimated that 584,000 deaths due to malaria have occurred (367,000–755,000) of which 78% were children under 5 years of age and 90% came from Africa; today, there are an estimated 3.2 billion people at risk of contracting the disease since are living in areas influenced by the disease, of which 1.2 billion are at high risk (more than 1 into 1000 possibility of acquiring malaria in the year); in the Region of the Americas, it is presumed that the risk is 120 million people in 21 countries in the region [5].
\nEradication efforts by public health preventive measures are not sufficiently effective for many reasons, among which are the socioeconomic, demographic and technical policies, emerging resistance to insecticides by the vector and to antimalarial drugs by the parasite [6]. In 2010, vector resistance had been reported in 49 countries around the world of which 39 reported resistance above two or more pyrethroid insecticides. In 2013, this report increased to 82 countries reporting insecticide resistance [3], therefore, to develop an effective vaccine against the disease becomes an urgent need.
\nBy 1967, major efforts were made to find an effective vaccine against human malaria, in one of the most important related studies of the time, 59% protection was achieved after an intravenous challenge of a malaria murine model after being vaccinated with 75,000 live attenuated irradiated sporozoites [7].
\nCurrently among vaccine candidates that are in more advanced clinical trials are the RTS,S and PfSPZ which incorporates the use of non-replicative attenuated sporozoites through controlled radiation [8], which has obtained a dose dependent protection in humans being necessary the application of 1.35 × 105 attenuated sporozoites in five doses [9]. It should be noted that the duration of protective antibodies has not been fully established, thus obtaining a vaccine is not a reality.
\nAs can be observed in Figure 2, global malaria spreading accounts for more than 80 countries that are affected by malaria infection (purple background in the map). Besides, insecticide susceptibility status for malaria vectors (Anopheles female mosquitoes) demonstrates a resistance increasing to most insecticides concomitant with areas of high transmission of malaria.
\nAreas of risk of malaria transmission and ongoing malaria vaccine candidate trials.
A deep knowledge and understanding of the Plasmodium parasite life cycle would be a key step towards antigen discovery, and it will establish the molecular basis for a proper immunogen designing to be further tested as a vaccine candidate. The Plasmodium spp. belong to the phylum Apicomplexa being the causative agent of malaria, whose clinical and pathological manifestations are associated with asexual erythrocytic stage of the parasite [10].
\nThere are five species of Plasmodium causing human malaria, the most lethal disease is caused by P. falciparum and followed by P. vivax, and less prevalent are Plasmodium malariae and Plasmodium ovale [11] in 2011 Plasmodium knowlesi was included in this list. In Colombia for the year 2014, 356 clinical cases of uncomplicated malaria were reported, 20,074 cases of malaria by P. vivax, 19,789 by P. falciparum, 17 cases by P. malariae and 561 cases of mixed malaria according to data presented by the National Institute of Health (INS) in its weekly report SIVIGILA [12].
\nPlasmodium parasites have a complex life cycle involving interactions of invertebrates (vector) and vertebrates (mammalian host), besides presenting various stages in intracellular and extracellular environments (Figure 3) [13].
\nPlasmodium life cycle. Main pre-erythrocyte, blood and sexual stages are denoted.
In the human host, sporozoites are inoculated by the bite of female Anopheles spp. mosquitoes, then invade hepatocytes in a time between 5 and 30 min; within hepatocytes each sporozoite develops a schizont which release between 10,000 ± 30,000 merozoites to blood stream during a period of 2 ± 10 days depending on the parasite specie [14], in the case of P. vivax and P. ovale also it produces a different stage in the liver called hypnozoite, which is a silent form responsible for the subsequent relapses [11]. During the travel from the skin to the liver, the parasites cross the capillary epithelium in the dermis and enter to blood circulation, cross the hepatic sinusoids epithelium to enter the parenchyma, and this process as the hepatocyte infection are given by activity of the myosin-actin engine located in the plasma membrane of the parasite and its rhoptries, dense granules and micronemes [15].
\nThe invasion of erythrocytes occurs after several steps with multiple interactions between receptor membrane proteins of host cells and parasite protein ligands expressed in its surface as well as in rhoptries and micronemes [16]. The parasite grows and divides in about 72–48 h according to the specie to the schizont stage which contains more than 30 merozoite particles, which are released with the subsequent invasion and replication in healthy erythrocytes [17]. Acquired immune response induced by malaria parasites is complex and varies depending on the level of endemicity, epidemiology, genetic, age of the host, parasitic stage and parasite species. Repeated infections and continued exposure are required to achieve clinical immunity with symptom reduction and reduced number of parasites in an infected individual or inhibition of parasite replication [18].
\nThe mouse model has been widely used in the study on malaria, and it has been regarded as a practical model for experimental studies since its genetical features regarding human beings such as homology and similarity at the protein structure level, physiology and life cycle besides of owning a malaria transmission vector (Anopheles stephensi) that can be maintained under defined laboratory [19].
\nDue to this, there are several Plasmodium strains that infect rodent models by malaria (P. berghei, P. yoelii, P. chabaudi, P. vincker), and their experimental behavior can be extrapolated due to the fulfillment of a standard life cycle under controlled conditions. The two most commonly employed strains in malaria vaccine discovery are the P. yoelii and P. berghei, which have high similarity with the clinical symptoms and pathology developed by P. falciparum in relation to those stages of cerebral malaria, placental malaria, severe malaria and organ damage as liver, kidney and lung [20]. The P. berghei infection model has allowed demonstrating the role of interferon in response to parasite replication in the liver, and this participation was then demonstrated in P. falciparum [20].
\nThe rodent malaria infection by P. yoelii has allowed to demonstrate that humans immunized with the PfCS protein from the parasite sporozoite stage, induced antibodies that cross-react with P. yoelii, as well as mice immunized with PyCSP stimulated antibodies that cross-react with P. falciparum; therefore, this model evidenced its usefulness as a predictive tool for immune response against certain malarial antigens since there are a 70% of genome similarity between P. yoelii and P. falciparum [14]. This similarity associate at least 3300 orthologous genes of P. yoelii with 5268 genes of P. falciparum [21]. Although the erythrocytic cycle of P. berghei and P. yoelii takes place more rapidly (24 and 18 h, respectively) compared to those developed in P. falciparum (36–48 h) and P. vivax (48 h), differences in tropism for invasion of reticulocytes in the case of P. yoelii and P. berghei are not presented in P. falciparum and the genetic similarity between these Plasmodium is quite important, and so the rate of increase in parasitemia levels is similar during the first 3–4 days after inoculation in vitro as well as the parasite growth [22]. Also, in vivo conditions and clinical symptoms associated to the disease are presented in terms of fever, malaise, splenomegaly and breathlessness related with red blood cells rupture which differ of symptoms present in infections with other strains such as P. chabaudi where in contrast the infection is associated with hypothermia [23]. The production and regulation in the cytokines expression are no exception to the similarity between the mouse model and a malaria human infection since P. yoelii and P. berghei replicate many events that can be correlated between both of the infection types [24, 25].
\nIn studies at the level of liver infection cycle were found that about 654 (92%) of proteins in P. yoelii correlated with orthologous sequences present in P. falciparum and 66% of the genes in the P. yoelii transcriptome have orthologues in P. falciparum [26]. Also in this stage of infection, it has been possible to obtain in vivo images in models of infection with P. berghei in mice, these have shown details of hepatocyte invasion by Plasmodium which were not yet known in humans, as well as the fact that sporozoites can recognize heparan-sulfate proteoglycans besides that P. yoelii infection models have been conducted to tests the oxidative stress in the liver induced by infected erythrocytic forms [27].
\nBearing in mind, the possibilities offered by murine infection models, we have conducted an important amount of experiments in order to test a variety of chemically modified antigens as potential vaccine components.
\nIn spite of impressive economic and political efforts conducted by WHO and other non-government organizations for malaria eradication and control, based on insecticide treatment of bed-nets (mainly DTT), use of new formulations of artemisinin and other antimalarials for treatment of infected patients and teaching about an appropriate water and environment care to inhabitants of malaria high-transmission areas, among other strategies, malaria still remains as one of the most important health problems for developing countries. Contrary to those expectations, most of these strategies have failed for malaria control, mainly due to novel and powerful biological evolution of antimalarials-resistance mechanisms developed by Plasmodium parasites, joint to the continuous mosquito adaptation and colonization of new environments and territories, climate changing and global warming due to non-controlled gas emissions to the atmosphere. Therefore, hopes for controlling this lethal disease are based on developing more efficient preventive strategies and highly potent malaria vaccines.
\nUp-to-date, about 236 including chemoprophylaxis and malaria vaccines clinical trials are being conducted worldwide, most of them have been completed showing a limited success (as shown in Figure 2). Most conducted studies have been focused on vaccine candidates aimed to block three different potential targets, being the transmission-blocking approach the first (gametocyte-derived proteins such as Pf25 and Pf125); secondly, those candidates directed against Plasmodium liver-malaria stages (considering proteins such as Circumsporozoite surface protein (CSP), liver stage antigen (LSA), sporozoite and liver stage antigen (SALSA), Thrombospondin-related anonymous protein (TRAP) and others) and vaccine candidates directed against malaria blood stages (classical merozoite protein targets are Merozoite surface proteins 1-10 (MSP-1-10), apical membrane antigen-1 (AMA-1), ring-infected erythrocyte surface antigen (RESA-155), serine repeat antigen (SERA), Erythrocyte binding antigen 175 (EBA-175) among others).
\nAs recently mentioned by Birkett in 2015, the European Medicines Agency announced a positive opinion for the malaria vaccine candidate most advanced in development, RTS,S/AS01, which provides modest protection against clinical malaria in all conducted trials, but in spite of its poor efficacy later in 2016, this product was recommended by WHO for large-scale trials in moderate to high malaria transmission areas [28]. As observed in Figure 2, 113 trials of pharmaceutical products among antimalarials and vaccine formulations are being conducted in Africa in high-transmission malaria regions by immunizing mainly with modified or attenuated sporozoite NF54 strain malarial parasites or other products such as the so-named biological PfSPZ vaccine all of them formulated on strong adjuvant systems such as AS01 as can be observed in the web site ClinicalTrials.gov, a service of the U.S. National Institutes of Health [29].
\nDue to the moderate success conducted in the last three decades of researching for finding highly potent vaccines for preventing malaria, the field is open for new ideas regarding the discovery of strategies for developing structurally modulated molecular probes which address the Plasmodium complex molecular mechanisms involved in parasite detection, facing the challenge of demonstrating protective efficacy profiles and parasite clearance capacity, so those would enter the pathway of being regarded as components of novel vaccine formulations.
\nMorbidity to malaria outside of the sub-Saharan Africa still remains meaningful causing more than 50% of malaria cases, especially in the Americas and Pacific-Asia where poverty and public health systems are associate to multiple problems. The complex P. vivax biology and its ability to differentiate into latent forms called hypnozoites which appear longtime later to produce erythrocyte infective forms, prompt occurrence of macro and micro gametes previous to clinical manifestations are seeming, and thus a short evolution cycle into the mosquito makes useless using standard tools to control P. vivax. Simultaneously to decreasing in global incidence, some dramatic changes in pathogen infective species have been reported by P. vivax being currently the prevalent Plasmodium spp. in those mentioned world regions.
\nFor multiple reasons, the epidemiologic spreading of malaria due to P. vivax is being regarded as careless. However, turning on attention to malaria caused by P. vivax has to be a priority when thinking in a vaccine against malaria. Most approaches for a P. vivax malaria vaccine candidate have considered orthologous sequences among the most predominant Plasmodium species as being P. falciparum and P. vivax especially antigens of both pre-erythrocyte and erythrocyte stages. Among a number of vaccine candidates, the VMP001/AS01 targets the CSP antigen of P. vivax. This has been assessed in controlled human malaria infection (CHMI) studies but proven to be unsuccessful with poor protection capacity. Another candidate, which is a recombinantly expressed on appropriate virus, targets the TRAP antigen and currently is currently in study and another prototype vaccine candidate is based on using the strategy of attenuated sporozoites.
\nOn the other hand, the most focused P. vivax erythrocyte-stage antigen is the Duffy binding protein (DBP), which is considered crucial for red blood cell (RBC) invasion; however, the DBP non-conserved character establishes an important hindrance. Importantly, time of protection against malaria would be more relevant for a P. vivax vaccine regarding a P. falciparum vaccine due to P. vivax disease incidence is not focused in given populations as it is for P. falciparum. Hepatic P. vivax-stages also contribute to reinforce this problem complexity [30, 31].
\nTherefore, developing potent P. vivax vaccines would depend on several key aspects among establishing a continuous P. vivax—culture in enriched reticulocyte media or specific growth factors aimed to reproducing parasite infections, also appropriate animal models for vaccine candidate testing and most importantly the right selection of multi antigen formulations in human adjuvants and delivery systems, thus peptido-mimetics would play a role in this pursuit.
\nIt is well known the fact that the T-cell receptor sees antigen on the surface of cells associated with an MHC class I or II molecule. Therefore, activating humoral and cell-mediated immune responses requires factors such as cytokines and costimulatory molecules expressed by Th cells. A fine and specific regulation of Th has to be highly regulated in order to avoid any self-reactivity would conduct to auto-immune disorders. In order to ensure the Th-cells activation and regulation, these have to recognize a given antigen that is being presented in the MHC class-II context which is located on an antigen presenting cell (APC) surface. As it is known, these professional presenting cells among macrophages, dendritic cells and B lymphocytes harbor two relevant features: (1) surface expression of class-II (MHC-II) molecules, and (2) recruitment of costimulatory molecules as signals for activation of Th-cells.
\nAntigen-presenting cells first internalize antigen, and then display a part of that antigen on their membrane bound to a MHC-II molecule. The TH cell recognizes and interacts with the antigen–MHC-II molecule complex on the membrane of the antigen-presenting cell. Immune system is prepared for antigen presentation by stabilizing MHC-II molecules in the endoplasmic reticulum bound to an endogen invariant Ii chain which is later cleaved to a small peptide called class II-associated invariant chain peptide (CLIP) which remains bound to the MHC-II molecule to be then replaced by a given antigen-peptide assisted by a chaperone molecule named HLA-DM in endosomal compartments. Therefore, the antigen-MHC-II bimolecular complex will travel to the APC membrane surface to be presented to T-cell receptors (TCR) of T-lymphocytes to establish and stabilize in consequence specific ternary complexes able to trigger CD4+TH cell proliferation and so an immune response.
\nAs mentioned one of the main functions of CLIP is to prevent the binding of self-peptide fragments prior to the MHC II localization within the endosome-lysosome, a consensus primary structure of CLIP is 87PVSKMRMATPLLMQA101, which is able to a proper interaction with a HLA-II molecule by anchoring-specific residues to the so-named pockets 1, 3, 4 and 9 of the MHC-II molecule in such a way that its entire structure will remain buried into the HLA-II molecule. The CLIP-HLA-II (CLIP: HLA-DR3) molecular complex is shown in Figure 4. As observed, the endogenous peptide is hidden into the presenting HLA-II molecule, and the possibility of being recognized by any TCR is completely abolished, and so an auto-reactive immune response will not take place, thus if a given pathogen can develop immune response evasion mechanisms based on its ligands structure features, it would be desirable to its convenience to resemble the most relevant structure characteristics of CLIP to avoid be recognized by TCRs [32].
\nAn endogen peptide-MHC-II bimolecular complex. The endogenous invariable Ii-chain cleaved CLIP product (87PVSKMRMATPLLMQA101) complexed to a HLA-DR3 allele. Coordinates of the CLIP-HLA-DR3 complex from the protein data bank (PDB) coded 1A6A corresponded to the structure determined by X-ray diffraction at a 2.75 Å resolution, was downloaded and molecular modeled with the visual molecular dynamics (VMD1.7ή) software of the University of Illinois at Urbana-Champaign. Color code representation for HLAII α-chain in purple, β-chain in cyan, HA peptide is represented in amino acid id code [32].
Influenza hemagglutinin (HA) or hemagglutinin is a glycoprotein found on the surface of influenza viruses. Its role is to bind the influenza viruses to their target cells through sialic acid, specifically to red blood cells and upper respiratory tract cells [33, 34]. Once the pH has been decreased, a second role of HA is to join the viral cover to formed endosomes. HA is an integral membrane glycoprotein expressed as homo-trimers which seem a barrel-like structure having around 13.5 nm in length. HA is confirmed by three monomers built into a alpha-helical core displaying spherical tips containing those sialic acid-binding motifs. HA is synthesized as monomeric units as precursor forms which are glycosylated and processed on protein maturation, to produce two shorter proteins called HA1 and HA2. The HA monomers are long helical chains attached to the cell membrane by HA2 and capped by HA1. Thus, HA has been responsible for stimulation of neutralizing antibodies which are proven to avoid influenza virus infection to its target cells, thus constituting an important molecular tool for infection control using mechanisms associated to ternary complex stabilization of HA-HLA-II α/β-TCR (CD4+) with specific HLA-DR4 alleles such as DRA*0101 and DRB1*0401 [34].
\nReactive and T-lymphocyte proliferation upon a stabilized ternary HA-hemagglutinin-HLAII-TCR complex. Coordinates of the human T-cell receptor (TCR) HA1.7, influenza hemagglutinin peptide, and major histocompatibility complex class II molecule, HLA-DR4 (DRA*0101 and DRB1*0401) were downloaded from the protein data bank (PDB) whose code 1J8H corresponded to structure obtained by X-ray diffraction at a 2.40 Å resolution, and then was molecular modeled with the visual molecular dynamics (VMD1.7ή) software of the University of Illinois at Urbana-Champaign. Color code representation for HLAII α-chain in purple, β-chain in cyan, HA peptide is represented in amino acid id code, TCR α-chain in yellow and β-chain in green [34].
Figure 5 recreates the 3D structure of the HA-hemagglutinin-HLAII-TCR ternary complex. As observed, the HA306–318 peptide backbone whose amino acid sequence is PKYVKQNTLKLAT anchor-specific residues into the HLA-II 1, 3, 4 and 9 pockets and clearly expose some residues in positions 5, 8 and 7 to be recognized by α/β-TCR chains and so stabilizing the molecular complex. However, the HA peptide binds promiscuously and can be presented by most of the frequently occurring DR alleles. Therefore, CD4+ T-lymphocyte proliferation would lead a subsequent neutralizing antibody production able to block the influenza virus infection, being this molecular interaction an effective mechanism effectively used for the immune response. As this a number of similar immuno-reactive complexes have been described [35–40].
\nCurrent prototype vaccines against malaria are failed to the goal of protecting any individual living in high risk malaria transmission areas even the most promising such as RTS,S which have less than 30% effectivity. As discussed above, the complex life cycle of Plasmodium parasites besides human genetic restrictions and immune mechanisms associated with protection makes obtaining an effective malaria vaccine a challenge. Therefore, obtaining new immunogens as vaccines and other molecular systems having potential application in malaria therapy would have to be with precisely selecting relevant antigens which would be submitted for steps of redesigning, production, formulation and in vitro tested before assayed in animal models; thus, after proven to be effective have to cross the border line for human clinical trials.
\nThe aim of our research is to produce back-bone modified immunogenic antigens which included non-natural elements such as chiral and peptide-bond substitutions directed to modulate the antigen 3D structure and stimulation of neutralizing antibodies. Our approach is based on low-polymorphic sequences of Plasmodium which are then modified into immunological relevant motifs as well as strategically including lysosomal substrates to stimulate processing and presentation steps on vaccinated individuals. Therefore, we have analyzed and produced representative modified immunogens based on a number of native sequences belonging to different stages of Plasmodium which upon vaccination of animal models have proven to be effective against malaria infection and parasite clearance [41–43].
\nOne of our first approaches for antigen peptide backbone modification consisted in introducing topochemical elements into the selected antigen primary structure, which consisted in two key features, first the amino acids chirality and second the peptide backbone space orientation. As represented in Figure 6A, the N-terminus low polymorphic region of the PfMSP142-61 native sequence (GYSLFQKEKMVLNEGTSGTA) was the base for evaluating the above described considerations. Thus, chirality impact on immunogenic properties was tested by introducing local and global l- and d-amino acid substitutions, and the peptide backbone orientation influence was assessed by reversing the primary structure but upholding its native composition. Therefore, a set of peptido-mimetic analogues were designed and synthesized and subsequently tested. As observed, the experimental group consisted in the PfMSP142-61 native sequence, entirely made of l-amino acids; its chiral D-analogue which preserved the sequence and was built with d-amino acids (represented in lowercase letters); another so-named Retro analogue sequence, which was constructed with d-amino acids and reversing the sequence orientation and an analogue called Retro-inverso, which was synthesized with l-amino acids and reversing the peptide sequence orientation. Also punctual or partially D-substitutions were include in the experimental group. CD profiles for the four molecules reflected interesting spectrophotometric properties, thus when comparing the native L-sequence (black line) with its D-enantiomer (red line), their CD profiles behave as specular images of one another as displayed in Figure 6B. Similarly, CD profile for the L-native sequence compared with that of the Retro-inverso analogue (green line), behave as mirror images of each other bearing in mind that both were made with only l-amino acids, but having opposite peptide backbone orientation.
\nChiral and topochemical peptido-mimetic designing. (A) Molecular peptido-mimetic design based on the N-terminus PfMSP142-61 peptide. The native sequence is represented in capital letters for l-amino acids, D-enantiomer represented by lowercase letters purple highlighted, Retro-sequence is constituted by d-amino acids in lowercase letters blue highlighted and the so-named Retro-inverso peptidomimetic is confirmed by l-amino acids green highlighted. (B) Circular dichroism secondary structure patterns for PfMSP142-61 peptido-mimetics. Used color code was black line for the native sequence, purple for its D-enantiomer, blue line for the Retro-analogue and green line for the Retro-inverso peptido-mimetic. Competition ELISA was used for the PfMSP142-61 peptide mapping with monoclonal antibodies coded Ig-αψ-437(52V-L53) and Ig-αψ-439(51M-V52) as shown in (C) and (D), respectively. IC50 μM values represent the average of data obtained in triplicate.
CD patterns for the D-enantiomer and the Retro-inverso analogue had a close relationship regarding the all-L native sequence. On the other hand, CD profiles for the all-D-enantiomer (red line) and the Retro-analogue (blue line) behaved as specular images of each other, keeping in mind that these molecules are made of only d-amino acids, having the second a reversed backbone regarding the first. Interestingly, CD patterns of both, the L-native sequence and Retro-analogue resemble each other but are opposite to the CD profile of the D-enantiomer. Therefore, a partial conclusion emerged from these findings, independently of the amino acid composition; backbone orientation seemed to play a key role for the 3D structure properties of the antigen molecule.
\nIn order to test the unique recognition of an antibody stimulated by a reduced amide peptido-mimetic in which the oxygen atom of the carbonyl group (–R–CO–NH–R′–) of a relevant peptide-bond was replaced with two hydrogen atoms to lead an analogue being the reduced form of it and herein named reduced amide peptido-mimetic ψ(–R–CH2–NH–R′–). Thus, two monoclonal immunoglobulins (mAb) were produced, one directed to PfMSP142-61 modified between the -52V-L53- and another directed to the -51M-V52- amino acid pairs, respectively, which herein are named as Igα-ψ-VL52-53 and Igα-ψ-MV51-52. Both mAbs possess inhibitory capacities in both in vitro and in vivo malaria infections by P. falciparum as well as P. yoelii and P. berghei as elsewhere published [42]. Also our experiments allowed to a fine mapping of the MSP-1 N-terminus portion using monoclonal and polyclonal antibodies induced by reduced amide peptido-mimetics of the PfMSP142-61 peptide and so we identified the antigen epitope whose amino acid sequence is 51MVLNEGTSGTA61 as elsewhere reported [44].
\nTherefore, a whole set of PfMSP142-61 modified analogues were used in competition assays for their ability to bind these mAbs. As observed in Figure 6C and D, the non-modified native sequence (all-L) bound at a 10 μg/mL while their inducer modified peptido-mimetics did it at a 1 μg/mL concentration. The reduced amide modification between 49E-K50 residues was an excellent competitor for binding to the Igα-ψ-MV51-52. Interestingly, the All-D-enantiomer and Retro-inverso form of the sequence behaved as strong competitors for the Igα-ψ-VL52-53 binding, both of them are built with d-amino acids. In a similar way, most partially made D-substitutions were strong binders to both tested antibodies. Thus, both chirality and back-bone orientation become critical properties for antigen-antibody recognition, considering that natural features have to be resembled in artificially-modified immunogens, as well as preserving the molecule structure topology but most relevant it is an appropriate side-chain space orientation, which will be crucial for binding and functional effects.
\nIn another set of experiments conducted based on the C-terminus low polymorphic portion the MSP1 antigen, the PfMSP11282-1301 peptide whose primary structure EVLYLKPLAGVYRSLKKQLE was the basis for protection capacity assays against malaria in Aotus monkeys immunized with reduced amide peptido-mimetics and partially made D-mutations. Animals were treated in agreement with Colombian and environmental regulations, and those individuals that developed malaria infection after being experimentally challenged with controlled doses of P. falciparum were subjected to medication to ensure their health conditions.
\nAs observed in Figure 7, a few number of animals vaccinated have controlled the Plasmodium parasitemia levels, especially two out of ten vaccinated with the reduced amide ψ-7P-L8 peptido-mimetic and four out of eight with a partial D-substitution in K6 of the PfMSP-11282-1301 sequence.
\nProtection capacity of PfMSP-1/1282-1301 peptido-mimetics. (A) Aotus monkeys immunized with the PfMSP-11282-1301 native sequence. (B) Animal group immunized with the ψ-9475 (7P-L8) reduced amide peptido-mimetic analogue. (C) Animals immunized with the partially substituted D-L8 analogue. (D) Group of animals immunized with the partially substituted D-K6 analogue. (E) Aotus monkeys immunized with saline solution as the placebo control group.
On the contrary, animals of the placebo-control and those vaccinated with the native sequence became faster infected and did not control the Plasmodium parasitemia. Therefore, the evidence supported the relevance of chiral-space occupancy as well as topochemical modifications as being important elements to be considered for malaria vaccine designing.
\nIn order to be consisting with our proposed molecular models, we decided to focus our attention in another relevant Plasmodium antigen, the so-named PfMSP-2 surface antigen. Specifically, we have designed and synthesized some reduced amide peptido-mimetics based on the N-terminus PfMSP221-40 peptide whose amino acid sequence is KNESKYSNTFINNAYNMSIR. Thus, two peptido-mimetic analogues coded ψ-128 and ψ-130 which were modified between the 30F-I31 and 31I-N32 amino acid pairs, respectively, were obtained and characterized. Our experiments for a fine PfMSP221-40 sequence mapping with monoclonal antibodies directed to both modified motifs have revealed a functional epitope whose exact location was 25KYSNTFIN32 as previously published [45].
\nAs observed in Figure 8, the reactivity patterns of both antibodies by western blot analyses lead to identified native PfMSP2 protein fragments stained at 30.54, 34.21 and 37.90 kDa on a P. falciparum FCB-2 membrane protein lysate. Faster polypeptide fragments of PfMSP2 on the SDS-PAGE, could be associated to this antigen cleavage during blood-stage parasite maturation to mature schizonts, previously to merozoite releasing (Figure 8A).
\nReactivity and functional properties of PfMSP221-40 peptido-mimetics. (A) Plasmodium falciparum FCB-2 membrane protein lysed resolved on a 7.5–15% SDS-PAGE gradient system. (B) Recombinant MSP2-(His)6 protein treated with the Ig-αψ-128 (30F-I31) monoclonal antibody. (C) Recombinant MSP2-(His)6 protein treated with the Ig-αψ-130 (31I-N32) monoclonal antibody. (D) Surface membrane proteins from blood stages of P. berghei treated with the Ig-αψ-128 and Ig-αψ-130 monoclonal antibodies. (E) Surface membrane proteins from blood stages of P. yoelii treated with the Ig-αψ-128 and Ig-αψ-130 monoclonal antibodies. (F) BALB/c mice infected with lethal doses of rodent malaria treated by passive transference of Ig-αψ-128 and Ig-αψ-130 monoclonal antibodies.
In order to verify the antibody reactivity, an Escherichia coli recombinantly MSP2 expressed fragment which contained part of the PfMSP2 N-terminus sequence was employed. Hence, the Ig-αψ-128 antibody detected lysate produced bands at 30.06 and 36.50 kDa and the Ig-αψ-130 antibody recognize bands at 34.71 and 35.50 kDa, all polypeptide bands contained the MSP2 recombinantly expressed fragment as compared with the control raw, as shown in Figure 8B, C respectively.
\nSimilarly, a lysate composed by membrane proteins from blood stages of P. berghei and P. yoelii were analyzed for these mAbs recognition. Therefore both Ig-αψ-128 and Ig-αψ-130 antibodies detected bands at 50.11 and 63.09 kDa mobilities for P. berghei ANKA and 44.46 and 50.11 kDa for the P. yoelii 17XL strain, respectively, as observed in Figure 8D and E. Besides, functional in vivo activity of these antibodies was tested by passive transferring experiments of both into P. berghei and P. yoelii infected BALB/c mice groups. Most animals survived to the lethal challenging with Plasmodium strains and efficiently have controlled parasitemia levels due to the antibody therapeutic activity as it was published and observed in Figure 8F [45]. This set of experiments revealed the importance of performing peptide-backbone strategic modifications by introducing non-natural elements into the immunogen primary structure, but its amino acid sequence identity has to be preserved to avoid any non-specific or non-desirable cross-reactive effects.
\nTo obtain a complete landscape of this novel scenario, further scopes of the strategy of obtaining next generations of malaria vaccine candidates based on introducing non-natural elements into immunogens, trials performed in selected antigens of other Plasmodium stages, such as those called pre-erythrocytic as well as sexual forms on macro and micro-gamete particles have to be conducted. Hence, the circumsporozoite surface protein (CSP) expressed on pre-erythrocyte forms offers a classical interesting target for vaccine candidate development.
\nAs reported before, a class-I restricted PbCSP252-260 epitope was identified in the CSP primary structure of Plasmodium berghei, a rodent malaria specie [46–49]. Thus, in order to test our hypothesis, we conducted experiments by introducing reduced amide peptide-bond isosteres in a systematic fashion and their subsequent evaluation regarding antibody stimulation and their reactivity was performed. This epitope whose amino acid sequence is SYIPSAEKI was the basis for the molecular designing. Thus, a set of peptido-mimetic analogues were synthesized and characterized. As shown in Figure 9B and C, antibodies induced by the PbCSP252-260 native sequence have some reactivity for both sporozoite and gametocytes as analyzed by indirect immunofluorescence assays (IFA) experiments while a stronger reactivity of the modified 257A-E258 amino acid pair of PbCSP257-258 peptido-mimetic-induced antibodies, become evident regarding both sporozoites and gametocytes as observed in Figure 9E and F. Antibodies of pre-immune sera did not show any reactivity as seen in Figure 9A and D.
\nExploring immunological properties of the restricted class-I PbCSP252-260 epitope by indirect immunofluorescence assays (IFA). (A) Pre-immune serum of mouse 2. (B) Plasmodium falciparum sporozoites detected by antibodies induced by the PbCSP252-260 native peptide post-third boost (mouse 2), image captured at 2 µm. (C) Detection of Plasmodium falciparum (NF54 strain) gametocytes by antibodies induced by the PfCSP252-260 native sequence post-third boost (mouse 2), and image recorded at 2 µm. (D) Reactivity of pre-immune serum of mouse 23. (E) Detection of Plasmodium falciparum sporozoites by antibodies to the PbCSP (A–E) peptido-mimetic obtained post-third boost (mouse 23), image recorded at 1 µm. (F) Detection of Plasmodium falciparum (NF54 strain) gametocytes by antibodies directed to the PbCSP (A–E) peptido-mimetic (mouse 23), and image captured at 2 µm.
The proposed hypothesis has been confirmed by challenging it in different molecular scenarios, all based on analysis of different antigens derived from different Plasmodium species and stages and proved in in vivo and in vitro assays. Thus, an emerging conclusion states the importance of a careful and strategic molecular designing of potential malaria vaccine candidates which consider the antigen global structure modulation but preserving their specific fingerprint represented by their amino acid sequence.
\nAimed to understand a possible structure-immunological activity relationship, a subsequent set of nuclear magnetic resonance NMR and molecular dynamic in silico experiments lead us to compare in all cases, both the native antigen, as well as their modified derivatives regarding their 3D structure properties. Thus, generated data are presented in Figure 10, in which either native antigen backbone conformation is overlapped with that of its functional representative peptido-mimetics or polypeptide conformations of homologue proteins in two Plasmodium species are compared.
\nStructure-immunological activity relationship. Overlapped backbone of native and modified peptido-mimetic analogues were organized as follow. (A) Accessible solvent surface of the PfMSP142-61 native sequence in white and ψ-437 in red ribbons and ψ-439 in blue ribbons. (B) Accessible solvent surface of the PfMSP11282-1301 native sequence, ψ-9473 in blue ribbons and ψ-9475 in red ribbons. (C) Accessible solvent surface of the PfMSP221-40 native sequence, ψ-128 in purple ribbons and ψ-130 in ochre ribbons. (D) Accessible solvent surfaces in white for PfCSP and blue for PbCSP. The 308SYIPSAEKI316 class-I restricted epitope is highlighted.
As observed in Figure 10A, overlapped 3D conformations of the N-terminus PfMSP142-61 peptide whose solvent accessible surface depicted in white, and two of its peptido-mimetics those coded as ψ-437 (52V-L53) and ψ-439 (51M-V52) represented by red and green ribbons, revealed deep structure differences between them. A highly compact α-helix structure present in the native sequence became flexible in its two peptido-mimetic analogues due to a single peptide bond modification, in which the oxygen atom of the –CO–NH– amide function of a specific peptide-bond, was replaced with two hydrogen atoms so leading –CH2–NH– surrogates.
\nSimilarly, backbone of the low polymorphic C-terminus of the same PfMSP1 antigen specifically the PfMSP-11282-1301 peptide fragment (solvent accessible surface in white) was overlapped with its two derive ψ-9473 (6K-P7) and ψ-9475 (7P-L8) peptido-mimetics (red and blue ribbons) [50]. As in the first analyzed case, a highly compact α-helix structure present in the native sequence became flexible in its two peptido-mimetic analogues due to single peptide bond modifications which surely have introduced new freedom degrees to the molecule, as seen in Figure 10B.
\nOn the other hand, backbone structural analyses for the PfMSP221-40 regarding its two ψ-128 (30F-I31) and ψ-130 (31I-N32) reduced amide peptido-mimetics, revealed a close-related behavior regarding the couple of the above discussed examples for a different Plasmodium protein, the PfMSP1. Figure 10C, displays the β-stranded conformation of the native sequence (solvent accessible surface depicted in white) regarding the more flexible conformations of both of its peptido-mimetics (represented by purple and ochre ribbons).
\nAn interesting observation become evident when backbone of two homologue proteins are overlapped regarding a class-I epitope region, as it was the case of the PfCSP and PbCSP, as shown in Figure 10D; consisted in that those overlapped polypeptide conformations, suggest an intermediate molecular state among them, which could be represented by a peptido-mimetic structure probe. Thus, the peptido-mimetic coded PbCSP252-260 which represents a peptide-bond surrogate located between the 257A-E258 amino acid pair, thus this strategic peptide-bond replacement could be responsibly of the stimulated cross-reactive antibodies.
\nFurther experiments in this pursuit will explore hypothesis on in vivo protection against malaria regarding CSP peptido-mimetics and will be conducted in order to assess the functional inhibitory activity of peptido-mimetics and their antibodies on malaria-infected mice through Anopheles albimanus mosquito bites.
\nThe family of the herein presented structural modified compounds constitute molecular tools to be considered for new generations of functional protective vaccines against malaria, as such, future vaccine candidates could be based on this knowledge and outstanding findings.
\nAs the author of this work, I am indebted to Prof. Manuel Elkin Patarroyo for his invaluable contribution to my personal view on the malaria vaccine field. Special thanks to the Colombian Science Technology and Innovation Department (Colciencias) (Grant No. 212456934488).
\nExtra-corporeal membrane oxygenation (ECMO) or extra-corporeal life support (ECLS) is quickly becoming a well-established form of therapy for patients presenting in severe respiratory failure and/or cardiogenic shock. The fundamentals of therapy, while technically challenging and involving a complex dynamic human-artificial circuit system, also requires a huge reliance on a multi-disciplinary team and an institutional infrastructure with robust administrative support at all levels to function effectively. While the medical and technical aspects of therapy are covered extensively in this text—and the others in this series [1, 2], a common fundamental question that is often asked is “how do we start and develop a program?” The development of an ECMO/ECLS program is far more complex than organizing a small group of interested providers and acquiring the hardware necessary for support—as such, the goal of this chapter is to outline those steps necessary to help establish a foundation for a successful institutional program.
\nAcute respiratory failure—regardless of the etiology—remains a complex and difficult problem to treat. Management focuses on treating the primary problem and allowing lung healing via lung protective ventilation strategies, while maintaining adequate oxygenation and ventilation [3]. Unfortunately, morbidity and mortality remain high in patients with severe lung injury, despite implementing standard lung protective strategies. Even for those patients who survive, quality of life can be severely impacted for many years after their initial illness [4]. Acute cardiac failure, or cardiogenic shock, also presents a difficult clinical problem for which even contemporary outcomes are less than ideal. While the most common cause of cardiogenic shock remains pump failure after an acute myocardial infarction, other mechanical problems such as acute papillary rupture (with acute mitral regurgitation), ventricular septal rupture, and myocarditis [5] must be considered [6]. While the use of ECMO for either acute respiratory failure or cardiogenic shock (or often a combination of both) is well-described, in part due to more comprehensive reviews of these topics elsewhere in this text, their incidence and challenges—regardless of the circumstances—serve as a foundation for why there is a substantial interest in developing and growing ECMO programs.
\nThere is growing evidence to support the role of ECMO in the management of these very difficult problems. ECMO has been shown to be an important tool in the armamentarium of any program that serves as a tertiary or referral center for complex cardio-pulmonary pathologies. In fact, excluding the survival benefit that has been demonstrated in patients who are supported with ECMO, there is also growing evidence to suggest that overall outcomes of patients with Adult Respiratory Distress Syndrome (ARDS) or cardiogenic shock treated at “ECMO Program Centers” are better regardless of whether they are treated with ECMO. In other words, the multi-disciplinary and administrative commitment to take care of patients (both adults and children) with complex and difficult cardiac and pulmonary problems can lead to improved outcomes independent of the actual use of ECMO [7, 8, 9, 10].
\nTwo randomized clinical trials in patients with severe ARDS support the implementation and increased utilization of ECMO therapy [11, 12]. These randomized trials—again, topics that will be discussed elsewhere in this text—despite their controversies, have demonstrated a clinical benefit of ECMO in the setting of ARDS. These well-conducted randomized trials, in addition to the extensive body of literature (case series, single center reports, and Extracorporeal Life Support Organization (ELSO) registry reviews—far too numerous to reference) combined with growing society guidelines and position papers, serve as a solid foundation of medical science to support the development of ECMO programs worldwide [13].
\nThe clinicians and administrators first determine the need and support for an ECMO program. This multidisciplinary group then operationalizes the care team that needs to be assembled and trained. The team includes clinical, administrative, ancillary, and other stakeholders, which are required to care for the patient and support the infrastructure, while moving the program to implementation.
\nPhysicians from Cardiothoracic Surgery, Pulmonary/Critical Care, and Cardiology form the foundation of physician support for veno-veno and veno-arterial ECMO patient identification, insertion, and management. In addition to the core physician team, there is a need to engage neurologists and infectious disease specialists to understand the therapy and the unique patient care challenges and complications associated with ECMO support. Vascular surgeons often will get involved with cannulation if others are not available or comfortable with placing large bore cannulas—likewise, there is a growing interest by general and trauma surgeons [14].
\nIn addition, the Palliative Care team must be involved from the very beginning of program’s development and some will advocate, especially in pediatric programs (while the focus of this chapter is on adult program development), Palliative Care providers are automatically involved and consulted on every ECMO case. As such, their understanding of the risks and benefits of ECMO are critical given the marginal outcomes associated with ECMO, even in the best of circumstances [15].
\nInclusion of emergency physicians in the team can assist with early identification of patients on presentation to the emergency room, and implementation of protocols in the emergency room for cardiogenic shock and respiratory failure [16].
\nAdministrators from the executive team should be engaged early to help support the creation of structures to accelerate implementation, project management, and assurance of adequate capital and personnel resources for a sustainable program. Financial models, which obviously vary from system (and country) to system, must be considered—and given the amount of resources required to establish and maintain an ECMO program, it is wise to have someone to monitor the financial implications.
\nRespiratory therapists assist with identifying possible candidates and work closely with the team ensuring the implementation of lung protective strategies. The growth of electronic medical records can allow for daily (if not more frequent) reports of those patients who might be considered for ECMO based upon ventilator settings and arterial blood case results.
\nPerfusionists must be engaged to help with setup, oversight of the ongoing treatment and for their skill sets in understanding the complexities of the machines and testing required.
\nFinally, there are implications for laboratory department around testing and blood bank needs; as well as coordinating and consulting with case management, ethics, and chaplains in regard to complex shared decision-making to implement, care for, and remove therapy; and the rehabilitation needs for patients post-ECMO removal.
\nIn addition to leadership described previously, executive nursing leadership, departmental nursing leadership, nursing advanced practice providers (APP), and frontline nursing engagement are fundamental and are essential to assure the success of the program. This includes communication, input and collaboration with policy, procedures and evidence-based protocols, education and competency training of high performing clinical staff, and provision of surveillance and care of patients. Frontline nursing from outside the ICU are often engaged in patient flow and early identification of decompensating acute care patients, who may need to be considered for ECLS. Since patients might require ECMO at any time, day or night, and given the amount of resources required to initiate and care for such patients, nursing administration must be involved to help develop protocols to organize “phone tree” lines of communication and specialized competent staff schedules to help recruit and arrange appropriate resources on very short notice.
\nAs the program grows beyond supporting the host hospital, it is necessary to engage Critical Care Transport to organize a system to transport patients from outside the facility with appropriate support and skill sets. This engagement is discussed more fully later in the chapter.
\nThe IT department can help with order set development and the Medical Staff office will need to support the development of privileging requirements to assure consistent skill sets for new team members.
\nEspecially in the situations with VA-ECMO use, long-term myocardial support may be needed. It is essential to build relationships with centers that can provide bridge to long-term LVAD support or transplant.
\nAdditionally, the marketing and public relations departments engage to help in creating materials to help outlying hospitals and physicians have awareness of the program, with knowledge of how to identify patients and when to transport to higher levels of care for consideration of ECMO support.
\nA rapid pace for implementation is best served by a strong triad leadership: experienced physician leaders and champions who are experts in ECMO; nursing leadership; and hospital executives. All need experience in change management and are given support and authority to use project tools and cross-functional influence to fast track project goals across a wide span of departments. These members then must communicate progress within the executive team.
\nFollowing Kotter’s change management theory, a small group of physicians, nursing leadership, and administrators gather to set a vision, determine the feasibility and challenges of the project, then create a shared project plan for the organization, structure, and timeline for implementation of the program [17]. The creation of a Gantt chart with key requirements and milestones is helpful in the early stages of program development—also useful in a sense of accomplishment and motivation of the team. Regular recurrent frequent meetings with agendas driven by a project management tool to assure progress is made on key deadlines, accountability to the individuals and team, and to create a shared message and plan for continued communication. Initial work should focus on best practice, research-based literature review, professional organization review of standards and data, then develop a gap analysis of clinical guidelines, equipment, skill sets, and organizational readiness. This small group should include Cardiothoracic surgeon(s), Pulmonologists, a “C” level executive, the cardiovascular service line, and Intensive Care nursing leadership. A small tactical group allows for more rapid progress through the initial stages and supports creation of a shared vision to accelerate momentum when the inevitable resistance to change surfaces—as well as working through team dynamics, comfort level, and building relationships. This group must strive to produce early wins, however small, to enable the organization to “feel the progress” as more difficult hurdles are faced. These can include shared clinical guidelines, order sets, and eventually patients that lived thanks to the program—as a true connect to purpose for all involved.
\nPutting screening guidelines in place and educating the teams on the benefits of ECMO to patients who would otherwise be terminal are very compelling when used in a story format.
\nFinally, change in management requires vigilance to newly implemented care processes, or the tendency of the organization will slide back to previous status quo. Tools and strategies that assist in holding on to new skills are most effectively done through audits, constructive timely feedback, continuous process improvement discussions, and accountability to the process. While education can assist in reminding staff of the “why”, it is not a sticky tool in terms of cementing new behaviors into a culture.
\nOnce the ECMO program is up and running, collaboration with the quality abstractionist and review of registry data at regular intervals generates quality improvement projects to assure new practice and clinical referral patterns producing the optimal outcomes. It is also a way of preventing politics and rumors from gaining momentum as the facts are reviewed and discussed in larger quality forums. These forums are ideally multi-disciplinary and followed up with tangible action items that have due dates and closed-loop communication back to the CQI team, as the action items are completed.
\nThe obvious hardware required for the program is the ECMO machine. The variables needed to make the correct choice for the program include need for portability of transport between facilities, as well as within the host organization, ease of use, skill sets of those responsible for managing the process, and the capital budget of the organization.
\nIn addition to the perfusion/ECMO machine, there is a need for a readily available stock of cannulas in various sizes, as well as for the variety of approaches that may need to be used. In addition, a well-stocked cart that allows the necessary equipment for sterile fields, cut-down, suturing, and possible complications of the cannulation procedures should be available to take to the patient’s location, as often the patient is not stable to transport to the OR for the procedure. As these are tools routinely used by perfusionists and cardiothoracic surgeons, they need to be engaged in selecting the appropriate sizes, manufacturers, connectors, introducers, wires and par levels. Many programs, as a function of the need to initiate ECMO therapy on short notice and in many different clinical areas, will create an “ECMO cart” which consist of all the key disposable equipment and tools needed to cannulate anywhere at any time (Table 1 and Figure 1).
\nSupplies | \nSize | \nRef # | \nQty | \n
---|---|---|---|
Cannulae: | \n\n | \n | \n |
Medtronic bio-medicus single stage venous | \n23Fr | \nCB96605-023 | \n×1 | \n
\n | 21Fr | \nCB96605-021 | \n×1 | \n
Medtronic bio-medicus multi-stage venous | \n25Fr | \n96880-025 | \n×1 | \n
\n | 21Fr | \n96880-021 | \n×1 | \n
Maquet avalon | \n31Fr | \n10031 | \n×1 | \n
\n | 27Fr | \n10027 | \n×1 | \n
Medtronic bio-medicus arterial | \n15Fr | \n96530-015 | \n×1 | \n
Medtronic bio-medicus nexgen arterial | \n17Fr | \n96570-117 | \n×1 | \n
\n | 19Fr | \n96570-119 | \n×1 | \n
\n | 21Fr | \n96570-121 | \n×1 | \n
\n | \n | \n | \n |
Wires/dilators/introducer kits: | \n\n | \n | \n |
Medtronic arterial introducer kit | \n\n | 96552 | \n×1 | \n
Medtronic venous introducter kit | \n\n | 96551 | \n×1 | \n
Lunderquist extra stiff | \n\n | G31453 | \n×1 | \n
Amplatz super stiff | \n\n | M0066401080 | \n×1 | \n
Sorrin dilator kit | \n\n | \n | ×1 | \n
4Fr micro puncture | \n\n | \n | ×4 | \n
4Fr introducer | \n\n | \n | ×1 | \n
6Fr introducer | \n\n | \n | ×2 | \n
8Fr Introducer | \n\n | \n | ×1 | \n
\n | \n | \n | \n |
Packs: | \n\n | \n | \n |
Basic pack | \n\n | \n | ×1 | \n
Angiography pack | \n\n | \n | ×1 | \n
\n | \n | \n | \n |
Suture: | \n\n | \n | \n |
Pledgets | \n\n | \n | \n |
2-0 Prolene SH | \n\n | \n | ×4 | \n
2-0 Prolene MH | \n\n | \n | ×4 | \n
3-0 Prolene SH | \n\n | \n | ×4 | \n
3-0 Prolene RB-1 | \n\n | \n | ×4 | \n
4-0 Prolene SH | \n\n | \n | ×12 | \n
4-0 Prolene RB-1 | \n\n | \n | ×12 | \n
4-0 Prolene large needle pledget | \n\n | \n | ×12 | \n
4-0 Prolene small needle pledget | \n\n | \n | ×12 | \n
5-0 Prolene C-1 | \n\n | \n | ×4 | \n
6-0 Prolene BV-1 | \n\n | \n | ×4 | \n
6-0 Prolene C-1 | \n\n | \n | ×4 | \n
7-0 Prolene BV-1 | \n\n | \n | ×4 | \n
#1 Sofsilk | \n\n | \n | ×6 | \n
0 Silk popoffs CT-1 | \n\n | \n | ×4 | \n
1 Vicryl CTX | \n\n | \n | ×2 | \n
0 Vicryl CTX | \n\n | \n | ×2 | \n
0 Vicryl CT-1 | \n\n | \n | ×2 | \n
2-0 Vicryl CT-1 | \n\n | \n | ×4 | \n
3-0 Vicryl SH | \n\n | \n | ×2 | \n
4-0 Vicryl PS-1 | \n\n | \n | ×2 | \n
4-0 Monocryl PS-2 | \n\n | \n | ×2 | \n
3-0 Ethibond SH | \n\n | \n | ×6 | \n
Heavy silk ties | \n\n | \n | ×4 | \n
2-0 Silk ties | \n\n | \n | ×4 | \n
3-0 Silk ties | \n\n | \n | ×4 | \n
4-0 Vicryl ties | \n\n | \n | ×4 | \n
2-0 Ethicon pacing wires | \n\n | \n | ×2 | \n
Orange pacing wires | \n\n | \n | ×4 | \n
Blue pacing wires | \n\n | \n | ×2 | \n
#6 Sternal wires | \n\n | \n | ×2 | \n
Double wires | \n\n | \n | ×2 | \n
\n | \n | \n | \n |
Prep: | \n\n | \n | \n |
Chloraprep | \n\n | \n | ×5 | \n
Duraprep | \n\n | \n | ×1 | \n
Alcohol bottles | \n\n | \n | ×2 | \n
PVP | \n\n | \n | ×2 | \n
CHG surgical scrub brush | \n\n | \n | ×5 | \n
\n | \n | \n | \n |
Blades: | \n\n | \n | \n |
#10 | \n\n | \n | ×10 | \n
#11 | \n\n | \n | ×10 | \n
#15 | \n\n | \n | ×10 | \n
Stryker sternal blade | \n\n | \n | ×4 | \n
Hall redo blade | \n\n | \n | ×2 | \n
\n | \n | \n | \n |
Umbilical tapes | \n\n | \n | ×8 | \n
Tourniquet 4 packs | \n\n | \n | ×6 | \n
Red vessel loops | \n\n | \n | ×2 | \n
White vessel loops | \n\n | \n | ×4 | \n
Shods 10 pack | \n\n | \n | ×2 | \n
Small yellow clip racks Qty 4 | \n\n | \n | ×5 | \n
Small red clip racks Qty 4 | \n\n | \n | ×5 | \n
Small automatic clip applier | \n\n | \n | ×1 | \n
Large automatic clip applier | \n\n | \n | ×1 | \n
\n | \n | \n | \n |
Asepto | \n\n | \n | ×2 | \n
Suction tubing | \n\n | \n | ×3 | \n
Cell Saver tubing | \n\n | \n | ×2 | \n
Yankauer tip | \n\n | \n | ×3 | \n
Poole tip | \n\n | \n | ×2 | \n
\n | \n | \n | \n |
Bovie pencil | \n\n | \n | ×2 | \n
Bovie pad | \n\n | \n | ×2 | \n
Long bovie tips | \n\n | \n | \n |
Short bovie tips | \n\n | \n | \n |
Eye cautery | \n\n | \n | ×2 | \n
\n | \n | \n | \n |
Snake clamp inserts | \n\n | \n | ×1 | \n
86 mm inserts | \n\n | \n | ×2 | \n
61 mm inserts | \n\n | \n | ×2 | \n
33 mm inserts | \n\n | \n | ×2 | \n
\n | \n | \n | \n |
Hemostatics: | \n\n | \n | \n |
Bone wax | \n\n | \n | ×6 | \n
Felt 4×4 | \n\n | \n | ×1 | \n
Felt 6×6 | \n\n | \n | ×1 | \n
GelFoam | \n\n | \n | ×1 | \n
Fibrillar | \n\n | \n | ×5 | \n
Snow | \n\n | \n | ×2 | \n
Nu-Knit | \n\n | \n | ×1 | \n
\n | \n | \n | \n |
Laps | \n\n | \n | ×9 | \n
Baby laps | \n\n | \n | ×5 | \n
Raytec | \n\n | \n | ×5 | \n
\n | \n | \n | \n |
Gowns | \n\n | \n | ×7 | \n
Towel packs | \n\n | \n | ×4 | \n
Gloves | \n\n | \n | \n |
\n | \n | \n | \n |
Drapes: | \n\n | \n | \n |
Split sheets | \n\n | \n | ×2 | \n
3/4 Sheets | \n\n | \n | ×6 | \n
Bi-Lat split sheet | \n\n | \n | ×1 | \n
Cardiac drape | \n\n | \n | ×1 | \n
\n | \n | \n | \n |
Tegaderms | \n\n | \n | \n |
4×4s | \n\n | \n | ×5 | \n
Esmark | \n\n | \n | ×1 | \n
Prineo | \n\n | \n | ×1 | \n
Stapler | \n\n | \n | ×1 | \n
Dermabond mini | \n\n | \n | ×5 | \n
Hollister horizontal tube attachment device | \n\n | \n | ×2 | \n
\n | \n | \n | \n |
18 Ga Hypo | \n\n | \n | ×4 | \n
Hep/blunt tip hypo | \n\n | \n | ×4 | \n
60 cc syringe | \n\n | \n | ×2 | \n
20 cc syringe | \n\n | \n | ×2 | \n
10 cc syringe | \n\n | \n | ×2 | \n
5 cc syringe | \n\n | \n | ×2 | \n
\n | \n | \n | \n |
Defib pads | \n\n | \n | ×1 | \n
Pacing cables | \n\n | \n | ×2 | \n
Decanters | \n\n | \n | ×2 | \n
Plasmalyte 1 L | \n\n | \n | ×2 | \n
ECMO cart supplies (sample).
(a and b): Portable ECMO cart that contains all the disposable tools needed for initiating therapy.
The ECMO team skill set crosses a variety of normal reporting structures within the hospital, as well as contracted services used in hospitals, including surgical services, nursing, laboratory, perfusion, physicians—employed and independent. Hence, thought must be placed into creating a strong team-based culture among a group of individuals who may have primary team affiliation across multiple departments.
\nThe use of multidisciplinary teams to develop project goals can serve as the first team building structure. Recognition of the team publicly can serve to bond the team more closely, and debriefings can prevent “silo formation” as individuals must often integrate in and out of the ECMO team due to patient volume and clinical needs. To cement this sense of team, the leaders of the departments that support the ECMO program should have regular meetings to discuss issues that arise, including productivity and interpersonal issues. Finally, the executive champion of the program should assure that there is accountability from all parties to the success of the program through goals and metrics, periodic meetings of the entire group of stakeholders, and shared public recognition of the successes of the program.
\nEarly in the development of any ECMO program, there must be a strategy for establishing “who watches what”—specifically, while nursing will always have bedside management of the patient, there must be consideration given as who has dedicated responsibility for the ECMO pump and circuit. As with any technology or “machine” that is directly connected to a patient—and provides critical life-saving support—there must be institutional guidelines and protocols regarding who monitors the functional status of the pump and circuit assuring safe and continuous functionality. In addition, the specific roles and responsibilities of this individual also need to be clearly defined. Various staffing models exist as described below.
\nPerfusionist is ideal bedside ECMO care providers, while initiating an ECMO program. Their advantages are considerable experiences in managing patients requiring extra-corporeal support as a function of their primary job responsibilities in the operating room supporting cardiac surgery procedures. Their training, credentialing, and licensure will often include formal experiences in managing patients requiring short-term mechanical circulatory support, including ECMO, outside of the operating room environment. A perfusionist-based model is appealing, however there are resource and financial limitations of this model. Perfusionists are usually limited in number (especially if they are also supporting an active clinical cardiothoracic surgical program) and their perspective is from a different care model which is focused around staffing limited time intervals in the operating room rather than 24/7 ICU-based ECMO care management. They are also an expensive resource for 24/7 daily ECMO use in the ICU. Given their availability and cost (and depending on how a program “employs” perfusionists—salary, per diem, hourly, contract employees, etc.), other care models are preferred for providing bedside ECMO support, particularly for veno-veno ECMO patients.
\nRN/RT ECMO specialist staffing models are becoming widely accepted and utilized in programs nationally—these programs and the combination structure of RT and RN staffing pools are mainly volume dependent to maintain competence. RNs have many advantages with regards to their inherent familiarity with the complexities and challenges in managing sick patients who require various life-support therapies. For example, in many programs, nurses manage renal replacement therapy technologies, wean and manage ventilators directly, and even have ownership in the management of both short- and long-term cardiac/ventricular support therapies. An additional advantage is, as a function such nurses are often extremely experienced in the management and assessment of critically-ill patients, they can serve as a valuable resource in other areas of immediate patient care—and potentially with volume and competence that become a primary care model for the more stable ECMO patient. Although respiratory therapists (RT) often have extensive experience in the management—and independent assessment—of patients requiring mechanical ventilatory support, it has only been relatively recently that their experiences and training in pulmonary mechanics and respiratory physiology, have they as a profession, been engaged as ECMO specialists. In theory, since most busy intensive care units are often staffed with a high volume of RNs and RTs, who are clinically high performing and engaged, the addition of monitoring ECMO pumps and circuits might not require a substantial investment in human resources and expanding staffing models. As such, using RNs and RTs might be viewed as being potentially less expensive—it is important to recognize that prior to using this human resource to monitor ECMO patients, a substantial investment in extensive ongoing education and training to maintain competence is needed. There are many courses offered by large ECMO programs, professional societies, and ELSO (see below) that can assist in the training of bedside ECMO specialists. Significant advantages in the ECMO specialist staffing model, already described as financially fiscal, also include continuity of nursing-based care provided by hospital staff who have an investment in the organization and unit, as well as the patients they serve.
\nAnother attractive option is a combination of various specialists—often as a function of the acuity of the patient and the needs of the program at any given time. Such a model takes advantage of the strengths of each type of healthcare professional. Even though such models can be difficult to implement as protocols defining individual roles and when and how handoffs can occur, nevertheless, with a strong collaborative team, a hybrid model can be successful. For example, for “routine” (if such exists) veno-veno cases of isolated respiratory failure in an otherwise hemodynamically stable patient, a perfusionist might help initiate therapy, provide the first 24 hours of support, and once the patient is deemed stable on ECMO, care is handed off to a RT or RN ECMO specialist. On-call perfusion support for technical questions and issues can then be easily provided from home and might not require immediate bedside support. Veno-arterial cases, especially in post-cardiotomy patients, might be more complex, and therefore might require more direct involvement of perfusionists given their experiences of managing such patients in the operating room. The challenge in a hybrid model is to determine either objectively or subjectively—the clinical parameters that would allow for an appropriate hand-off between one type (or level) of provider to another (i.e. perfusionist to RN/RT ECMO Specialist).
\nRegardless of the care model provided, there must be collaboration between the team members to build evidence-based standardized protocols, as well as strong physician buy-in in terms of supporting the individuals who manage the patient and pump at the bedside. Availability for immediate communication, using current technology, should be established between the ECMO specialist and/or perfusionist and the in-house physician. In addition, a strong and collaborative relationship between the ECMO specialist, perfusionist, and the bedside nurse must exist. Everyone must work together—inter-personality or professional conflicts cannot be tolerated and only get in the way of safe and effective patient care. Strong provider leadership, such as a perfusionist team leader, can be extremely effective in helping mentor other providers and serving as a resource for some of the day to day challenges in the management of an ECMO pump and circuit that might involve various disciplines, each of which have various levels of training and experiences.
\nIn addition, while current ECMO pumps and circuits are much more reliable than previous technologies, they will often have more advanced monitoring options. Each specialist involved in the care of the patient must have extensive training and a sound understanding of the functionality and troubleshooting of the entire circuit. Simulation training, as discussed in other chapters, plays a critical role in education and maintaining proficiency and, therefore, should be a key component—when feasible—of every ECMO program.
\nIn a multiple hospital system of care, there is not generally a need for more than one ECMO center for the system to accommodate the needs for non-CT surgery-related ECMO support. A helpful resource to assure patients have rapid transfer to the ECMO program from other hospitals, it is useful to set up a access center process to assure a standardized approach to hand-offs, transport, and tracking of patient movement. Call system personnel trained in the indications for ECMO can assist critical access and other facilities in routing possible ECMO patients for evaluation at the Center of Excellence. Early coordination with the call center leadership will allow them time to develop protocols, education, and coordination with transport services to assure smooth operations when the first patient call is received (Figure 2).
\nPatient access/call center flow.
A question that is often asked early in the development of any ECMO program is “where the patients should be cannulated?” While each institution must identify the ideal location for ideal cases, it is critical to recognize the nature of ECMO often dictates therapy must be able to be initiated anywhere within the hospital, including, but not limited to the following locations:
Emergency department
Operating rooms (cardiac and non-cardiac)
Catheterization labs
Obstetric labor and delivery suites
Intensive care units (medical, cardiac, surgical, neuro, etc.)
In fact, depending on the resources available and the resilience of the team, some centers will often consider initiating therapy in unusual out-of-hospital locations with the extreme example being the recent initiation of ECMO in the Louvre Museum in Paris, France [18].
\nPrior to considering the ideal location for initiating therapy, it is critical to outline those technologies that might be required. As discussed above, while it is important to have an “ECMO Cart” that contains, in a single location, all the key disposables that might be required, there might be a need for less portable equipment. For example, for cannulation, physicians might need immediate access to fluoroscopy and/or transesophageal echocardiography. Such technology might only be readily available in an operating room or catheterization lab. As many operating rooms, especially major trauma centers, and cardiac catheterization laboratories that support STEMI programs will often have access to advanced imaging, the exact ideal location often is dictated not only by physician preference, but also by potential administrative considerations. Such administrative considerations include the availability of a team to support cannulation, how disruptive emergency ECMO cases would be to the scheduling and allocation of OR/Cath lab resources, and often “how comfortable” the team is with the procedures. For example, Cath lab teams who are more comfortable with the catheter and wire-base procedures than surgical team might be a better option for peripheral cannulation of ECMO (arterial and venous)—while operating room teams might be better skilled at assisting with central cannulation (especially if the chest is already open). Nevertheless, a core “ECMO team” of providers beyond physicians and perfusions must be identified and included in all communications so that therapy can be initiated efficiently and safely anywhere needed.
\nOrder sets provide a rapid, standardized, initiation for ECMO. The order set should include guidance for the perfusion team and nursing team to appropriately care for the patient in a variety of settings, as well as give parameters for physician notification to address changes in patient status quickly.
\nOrder set elements should include:
Instructions for ECMO machine priming
ECMO circuit settings
ECMO daily parameters
Instructions for the perfusionist/nurse in charge of the machine
Instructions to leave all catheters in if not functioning and notify physician
Ventilatory settings
Blood products and transfusion parameters
Massive transfusion protocol parameters
Post-cannulation radiology studies
AP abdomen post-cannulation
AP chest post-cannulation
Radiology ◦studies
Echocardiogram for symptoms
Daily and routine laboratory studies
Anticoagulation and associated laboratory monitoring and adjustments
Triggers for notification of the ECMO physician/nurse practitioner
Other
Nursing care
Sedation medications
Physical therapy
Occupational therapy
Case management
Routine ICU parameters
Critically ill patients requiring ECMO can be transported by ground, helicopter, and fixed wing aircraft. Considerations in choice of transport include distance, number of team members required, equipment, electrical and oxygen needs, and cost. Ideally, patients can be identified and transported prior to initiation of ECMO therapy, however there are models of care with good results in which the team goes to the patient and initiates ECMO, and then the patient is transported to the ECMO center.
\nPer the 2015 ELSO guidelines, team members will vary depending on the need to cannulate the patient [19]. An ECMO specialist physician is required in either case, as is an ECMO specialist and a transport RN/RT. If cannulation is required, and the ECMO specialist physician is unable to perform this, there may be the need to add a cannulating physician and a surgical assistant to the team. Each team member has specific roles that should be delineated and understood prior to deployment to the outlying facility.
\nA checklist, should include all the needed equipment for the return trip with the patient, and should be verified prior to departure.
\nThe equipment recommended by ELSO includes [20]:
Suitable blood pump, centrifugal, or roller
Membrane oxygenator, appropriate for the patient size
Device(s) for heating and regulating circuit blood temperature (less critical for adult transports)
Medical gas tanks, regulators, hoses, connectors, flow meters, and blenders for provision and adjustment of blended sweep gas to the oxygenator
Venous and arterial pressure monitoring device(s), according to center-specific practices
Point-of-care anticoagulation monitoring equipment (e.g., activated clotting time)
Emergency pump or manual control mechanism in the event of primary pump failure or power failure
Uninterruptible power source(s) capable of meeting the electrical power needs of all equipment during transfer between vehicles and in the event of vehicle power source failure.
Portable ultrasound machine, if not provided by the referring facility
Additional equipment recommended by 2015 ELSO to improve safety includes:
System for servo-regulation of flow to balance venous drainage rate from the patient and blood return to the patient
Blood flow rate monitor (may be internal or external to the blood circuit)
Monitor(s) for circuit blood temperature, blood gas, oxygen saturation, and hemoglobin (may be internal or external to the blood circuit)
Capacitance “bladder” incorporated into the circuit
Bubble detector with or without automatic pump regulation function
Of note, the requirements for voltage, current, and power for all equipment should be verified for the transport vehicle prior to departure and monitored throughout transport. An adequate oxygen source must also be available with sufficient reserve to support high-flow 100% oxygen delivery for the duration of the transport. Provisions must be made to adequately secure the equipment during transport—brackets, holders, straps, etc. should be tested prior to first-time transport and should be compliance with appropriate regulatory guidelines (i.e., Federal Aviation Administration for the United States) (Table 2).
\nMethod of transport | \nAdvantages | \nDisadvantages | \nDistance for transport | \n
---|---|---|---|
Ground | \n\n
| \n\n
| \nUp to 300 miles | \n
Helicopter | \n\n
| \n\n
| \nUp to 450 miles | \n
Fixed wing | \n\n
| \n\n
| \nUnlimited | \n
Decision-making for ECMO transport options.
No patient should be transported without a means of manually providing circuit flow in the event of an electrical pump failure or malfunction.
\nAs with all areas of medicine, the optimization of patient outcomes must be a priority. This concept is especially important in the context of developing and maintaining an ECMO/ECLS program. Many other disease therapies have an infrastructure for monitoring clinical outcomes and benchmarking them against peer groups, national, and even international programs. These infrastructures typically are in the form of voluntary registries and databases (although some might argue that participation is becoming less and less voluntary and more and more a requirement—especially are payor sources are starting link payments to participation and eventually outcomes in such programs). Examples of these types of programs include the Society for Thoracic Surgeons (STS) Outcomes database (
Currently, the Extracorporeal Life Support Organization (ELSO) provides a mechanism for tracking and benchmarking outcomes for ECMO programs (
In addition to submitting clinical patient and outcome data for benchmarking to ELSO, programs should also establish a formal case presentation and review process. Much like traditional surgical “morbidity and mortality” reviews, given the high-acuity and resource intensive nature of ECMO, similar periodic reviews of institutional ECMO outcomes should also be reviewed. While the focus should not be in individual practices or decision-making, ideally, each case should be reviewed by the team in a non-judgmental fashion to explore for potential areas of opportunity. Likewise, while good outcomes should be discussion in the context of “what went right”—such cases should also serve as team learning opportunity for growth and improvement. Depending on the number of cases performed, such meetings should be held in a timely manner (monthly, quarterly, etc.) so that real-time assessments can be performed and the nuances of each case might still be relatively fresh in the minds of the providers. While the structure of such meetings can be variable, many “quality” meetings typically will only involve key stakeholders—both providers (i.e. physicians, ECMO specialists, perfusionists, etc.) and appropriate administrators. The benefit of having meetings limited is that there is then the opportunity for open, honest, and transparent conversations—either on a case-by-case basis or from a programmatic standpoint—in a manner that can and should be protected from legal disclosure under the umbrella of a formal peer-review or quality improvement initiative. Appropriate protections of patient data and provider involvement must be maintained and established from the onset.
\nLikewise, summary data of program outcomes—such as the number of cases, types of cases, and overall outcomes should be actively tracked in real-time and made available to institutional leadership as a gauge of program growth and success. Institutional leadership/administration should also be able to provide financial data as profit/loss margins must be tracked in the context of program growth and success. Additional benchmarking information should also be considered and tracked in real-time to help monitor the evolution of a program—and should include, but not necessarily be limited to:
\n(1) Patient demographics (i.e., age, gender, and major comorbidities)
\n(2) Primary indications for support and etiologies of respiratory failure and/or cardiogenic shock
\n(3) Type of support (VV, VA, eCPR, and cannulation)
\n(4) Duration of support
\n(5) Blood and blood product utilization
\n(6) Outcomes
Successful weaning from support
Death on support
Death despite successful weaning
Major factors contributing to patient death (i.e., multi-organ failure, neurologic, etc.)
Such summary data should be in addition to the extensive amount of clinical and circuit data that is collected and tracked in the ELSO registry (see above).
\nAs discussed above, the tracking of outcome data should be a key component to helping measure program growth and success. Such initiatives must be established from the onset and involve the program champions—both clinical and administrative leaders to be successful. While it is important to review cases in the context of tracking outcomes—both good and bad—from a programmatic standpoint, it is also important to examine outcome summary data with the focus of exploring potential opportunity for improvement. It should be a primary objective of the ECMO team to consider periodic continuous quality improvement (CQI) activities. The activities should be viewed as opportunities to review best practices, current literature on various topics, and metrics with the focused goal of improving outcome metrics—while the primary focus should always be on improving patient survival, other metrics, program practices, and guidelines should also be considered as topics for review. Key topics can be identified, champions identified, and a timeline established for review and the development of potential action plans. While the specific details of how to develop and implement CQI is out of the scope of this topic—it does emphasize the importance of engaged administrative leadership individuals and team who have established experiences with these programmatic and institutional activities. By no means, comprehensive, various CQI topics are listed in Table 3.
\nTopics for review | \nPotential desired outcome | \n
---|---|
Anticoagulation protocol | \nReduction in bleeding and bleeding related complication. Reduction in blood product utilization | \n
Antibiotic utilization | \nIntegration in an antibiotic stewardship program Reduction in multi-drug resistant infections Reduction in opportunistic infections | \n
Time from admission/intubation to initiation of ECMO support | \nPotential impact on improving weaning and survival outcomes | \n
Mortality despite successful weaning from ECMO | \nImproving overall outcomes and survival to discharge. | \n
Medication utilization | \nOpportunities for potential cost savings | \n
Family/patient satisfaction scores | \nOpportunities to improve communication with families, Improved satisfaction metrics | \n
Suggested topics for continuous quality initiatives.
Once the complex set of internal processes, personnel, and patient care skills are established, the ECMO program has the potential to serve patients in a wide area around the ECMO center. To assure that other hospitals and emergency facilities have the information to know of the resources available, and when to engage them, the primary facility should engage a multi-pronged approach to raise awareness and clinical decision-making skills of potential patient care partners. As with all endeavors, this should be done in the WIIFM (What’s In It For Me) with the patient and practitioner at the outlying facilities interests’ in mind. A good place to begin this is to address the benefits to the patient, the current science that supports the need for ECMO, the parameters for consideration of ECMO support, the process to easily move the patient, and the resources to enhance education of the topic. This is accomplished by marketing informational materials, individual outreach to create awareness, an education program that includes lectures, publication of successes, a plan for follow-up communication to the referring institution to help them understand the results of their referrals, and finally, by creating branding that helps the referral sources easily retain a connection to the program.
\nMarketing materials should ideally be created to reflect the ECMO program as a larger system of care around ARDS and shock. In addition to the organization housing the ECMO program, clear guidance on referral processes (see Call Center Section), there should also be some succinct explanation of the use of VV and VA ECMO, parameters for initiation of referral, as well as references to studies supporting the decision. Consideration should be given to having two sets of guidance; one for critical access lower acuity facilities/ER’s and one geared toward facilities with ICU care directed by intensivists, as the threshold for referral will be different.
\nThe personal touch of a visit cannot be underestimated when establishing trusted referral center status for complex procedures such as ECMO. It affords a chance to create personal trust, as well as allowing answers to questions are procedures and processes for transfer, and expectations for communication regarding patient status from the ECMO center. The outreach should be well versed on all of these processes, as well as having the ability to provide physician to physician conversations to answer any outstanding issues.
\nEducation is a valued commodity for referring physicians and clinicians when learning a new resource for their patients. The education can include multiple formats to meet the needs of the audience including lectures, educational brochures, webcasts, publications regarding outcomes and patient stories, and conferences at the ECMO center on topics related to ECMO such as current ARDS and shock therapies.
\nWhile clearly an avenue to enhance education, follow-up communication is also an important tool to create the interpersonal relationship that develops trust between the organizations. It is very important for referring provider to learn the “end of the story” regarding patients that were sent for therapy. In addition, this provides a transition of care so that appropriate ongoing care can be provided to the patient in their home medical community. This also establishes that trust of the referring providers that patients sent for a specific therapy will be sent back to the home community for the care that can be provided in that setting.
\nAs the use of ECMO increases, the need to create a memorable brand for the program becomes a key component to establishing the reputation of the ECMO center that is distinguishable from other future programs. The program should ideally be branded as a part of the larger cardiothoracic-vascular/pulmonary/critical care program of the institution. This allows the halo of the organization’s programs to create synergistic enhancement quality outcomes and growth opportunities.
\nThe initiation of an ECMO program is a comprehensive multidisciplinary project, which must be based on the clinical needs of the patients served. It requires advanced clinical capabilities and decision-making, and clear pathways for patient care to make it high quality and financially sustainable. As such, strong leadership is needed from physician leaders, nursing leaders, and administrative leaders working in a triad professional leadership model.
\nOnce the clinical case for implementation is made, a multidisciplinary team should be identified, and given the ability to work across multiple departments and stakeholders to assure all quality and operational details are aligned and accomplished. The team is encouraged to work using change management format and techniques supported with strong project guidelines to assure that the internal and external resources needed to support ECMO care are identified, captured as project goals, and systematically completed prior to initiation of ECMO patient care. Use of tools such as order sets, access center protocols, and education tools support clinical standardization across the team, and provides a consistency of clinical care.
\nQuality metrics are identified at project initiation and can be supported by ELSO tools allowing comparisons across programs internationally. The commitment to high quality and a relentless curiosity to find improvements that can be made, are critical to provide best practices to this high acuity population. The data and outcomes collected can help educate and encourage referrals from other programs that do not have ECMO capabilities, thus providing added advanced patient care options on regional basis.
\nThe literature has previously benchmarked an 18 month ramp up to program initiation as rapid deployment. Using the tools provided by others in the literature, a strong triad leadership process, and a dedicated multidisciplinary team with strong project management support, it is possible to accomplish program initiation in a six-month period in a hospital with an established CV Surgical program. We believe this process is replicable, and provides tools and implementation models that can be used by other hospitals to add needed ECMO support to meet their community needs [8, 9, 10].
\nEdited by Jan Oxholm Gordeladze, ISBN 978-953-51-3020-8, Print ISBN 978-953-51-3019-2, 336 pages,
\nPublisher: IntechOpen
\nChapters published March 22, 2017 under CC BY 3.0 license
\nDOI: 10.5772/61430
\nEdited Volume
This book serves as a comprehensive survey of the impact of vitamin K2 on cellular functions and organ systems, indicating that vitamin K2 plays an important role in the differentiation/preservation of various cell phenotypes and as a stimulator and/or mediator of interorgan cross talk. Vitamin K2 binds to the transcription factor SXR/PXR, thus acting like a hormone (very much in the same manner as vitamin A and vitamin D). Therefore, vitamin K2 affects a multitude of organ systems, and it is reckoned to be one positive factor in bringing about "longevity" to the human body, e.g., supporting the functions/health of different organ systems, as well as correcting the functioning or even "curing" ailments striking several organs in our body.
\\n\\nChapter 1 Introductory Chapter: Vitamin K2 by Jan Oxholm Gordeladze
\\n\\nChapter 2 Vitamin K, SXR, and GGCX by Kotaro Azuma and Satoshi Inoue
\\n\\nChapter 3 Vitamin K2 Rich Food Products by Muhammad Yasin, Masood Sadiq Butt and Aurang Zeb
\\n\\nChapter 4 Menaquinones, Bacteria, and Foods: Vitamin K2 in the Diet by Barbara Walther and Magali Chollet
\\n\\nChapter 5 The Impact of Vitamin K2 on Energy Metabolism by Mona Møller, Serena Tonstad, Tone Bathen and Jan Oxholm Gordeladze
\\n\\nChapter 6 Vitamin K2 and Bone Health by Niels Erik Frandsen and Jan Oxholm Gordeladze
\\n\\nChapter 7 Vitamin K2 and its Impact on Tooth Epigenetics by Jan Oxholm Gordeladze, Maria A. Landin, Gaute Floer Johnsen, Håvard Jostein Haugen and Harald Osmundsen
\\n\\nChapter 8 Anti-Inflammatory Actions of Vitamin K by Stephen J. Hodges, Andrew A. Pitsillides, Lars M. Ytrebø and Robin Soper
\\n\\nChapter 9 Vitamin K2: Implications for Cardiovascular Health in the Context of Plant-Based Diets, with Applications for Prostate Health by Michael S. Donaldson
\\n\\nChapter 11 Vitamin K2 Facilitating Inter-Organ Cross-Talk by Jan O. Gordeladze, Håvard J. Haugen, Gaute Floer Johnsen and Mona Møller
\\n\\nChapter 13 Medicinal Chemistry of Vitamin K Derivatives and Metabolites by Shinya Fujii and Hiroyuki Kagechika
\\n"}]'},components:[{type:"htmlEditorComponent",content:'This book serves as a comprehensive survey of the impact of vitamin K2 on cellular functions and organ systems, indicating that vitamin K2 plays an important role in the differentiation/preservation of various cell phenotypes and as a stimulator and/or mediator of interorgan cross talk. Vitamin K2 binds to the transcription factor SXR/PXR, thus acting like a hormone (very much in the same manner as vitamin A and vitamin D). Therefore, vitamin K2 affects a multitude of organ systems, and it is reckoned to be one positive factor in bringing about "longevity" to the human body, e.g., supporting the functions/health of different organ systems, as well as correcting the functioning or even "curing" ailments striking several organs in our body.
\n\nChapter 1 Introductory Chapter: Vitamin K2 by Jan Oxholm Gordeladze
\n\nChapter 2 Vitamin K, SXR, and GGCX by Kotaro Azuma and Satoshi Inoue
\n\nChapter 3 Vitamin K2 Rich Food Products by Muhammad Yasin, Masood Sadiq Butt and Aurang Zeb
\n\nChapter 4 Menaquinones, Bacteria, and Foods: Vitamin K2 in the Diet by Barbara Walther and Magali Chollet
\n\nChapter 5 The Impact of Vitamin K2 on Energy Metabolism by Mona Møller, Serena Tonstad, Tone Bathen and Jan Oxholm Gordeladze
\n\nChapter 6 Vitamin K2 and Bone Health by Niels Erik Frandsen and Jan Oxholm Gordeladze
\n\nChapter 7 Vitamin K2 and its Impact on Tooth Epigenetics by Jan Oxholm Gordeladze, Maria A. Landin, Gaute Floer Johnsen, Håvard Jostein Haugen and Harald Osmundsen
\n\nChapter 8 Anti-Inflammatory Actions of Vitamin K by Stephen J. Hodges, Andrew A. Pitsillides, Lars M. Ytrebø and Robin Soper
\n\nChapter 9 Vitamin K2: Implications for Cardiovascular Health in the Context of Plant-Based Diets, with Applications for Prostate Health by Michael S. Donaldson
\n\nChapter 11 Vitamin K2 Facilitating Inter-Organ Cross-Talk by Jan O. Gordeladze, Håvard J. Haugen, Gaute Floer Johnsen and Mona Møller
\n\nChapter 13 Medicinal Chemistry of Vitamin K Derivatives and Metabolites by Shinya Fujii and Hiroyuki Kagechika
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