",isbn:"978-1-83968-924-6",printIsbn:"978-1-83968-923-9",pdfIsbn:"978-1-83968-925-3",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"ea4ec0d6ee01b88e264178886e3210ed",bookSignature:"Dr. Hiran Wimal Amarasekera",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/9500.jpg",keywords:"Bone Tumors, Oncology, Childhood Tumors, Cancer, Risk Factors, Modern Management, Benign Lesions, Tumor-Like Conditions, Immunology, Histochemistry, Cell Oncology, Tumor Markers",numberOfDownloads:473,numberOfWosCitations:0,numberOfCrossrefCitations:1,numberOfDimensionsCitations:1,numberOfTotalCitations:2,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"September 28th 2020",dateEndSecondStepPublish:"October 26th 2020",dateEndThirdStepPublish:"December 25th 2020",dateEndFourthStepPublish:"March 15th 2021",dateEndFifthStepPublish:"May 14th 2021",remainingDaysToSecondStep:"6 months",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:"Consultant Orthopaedic Surgeon from Sri Lanka currently working in University Hospitals of Coventry and Warwickshire, UK, trained at the National Hospital of Sri Lanka, at the Oldchurch Hospital in Essex UK and The Avenue Hospital Melbourne, Australia and University Hospitals of Coventry and Warwickshire, UK, obtained the FRCS from Royal College of Surgeons of Edinburgh, Scotland.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"67634",title:"Dr.",name:"Hiran",middleName:"Wimal",surname:"Amarasekera",slug:"hiran-amarasekera",fullName:"Hiran Amarasekera",profilePictureURL:"https://mts.intechopen.com/storage/users/67634/images/system/67634.jpg",biography:"Hiran Amarasekera is a Consultant Orthopaedic Surgeon from Sri Lanka currently working in University Hospitals of Coventry and Warwickshire, the UK as a hip preservation fellow. \r\nHis special interests include young adult hip and knee problems, sports injuries, Hip and knee arthroplasty, and complex arthroscopic procedures. \r\nHe completed the MBBS from Kasturba medical college Manipal, India and did his postgraduate in Trauma and Orthopaedics at the Post-graduate Institute of the Medicine University of Colombo obtained the MS. \r\nHe was initially trained at the National Hospital of Sri Lanka and then completed the further training at the Oldchurch Hospital in Essex UK and The Avenue Hospital Melbourne, Australia and University Hospitals of Coventry and Warwickshire, UK.\r\nHe obtained the FRCS from Royal College of Surgeons of Edinburgh in 2003 and was elected a fellow of Sri Lanka College of surgeons (FCSSL) 2012. \r\nHe has a keen interest in academia and research. 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\n
1. Introduction
\n
Non‐pulmonary management of newborns with respiratory distress syndrome (RDS) is neither the last nor the least important part of the management, but it is supposed to be involved and intertwined in the whole necessary work‐up integrated for the well‐being of the tinny newborn. Each momentum from the prenatal care, pregnancy, and finally to the birth of the newborn should be considered when we are aiming to improve the final outcome, that is, delivery of a healthy newborn. Pulmonary management of newborns with RDS is only one, though very important and lifesaving, but not sufficient and adequate part of the whole care management of the newborns with RDS.
\n
\n
\n
2. Methods
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This chapter will look at the importance of prenatal care, temperature control, control of hypoglycemia, fluid and nutritional intake, the impact of perinatal infection and the use and misuse of antibiotics, frequency of unnecessary procedures, proper pain management, the impact of excessive use of opiates on ventilation duration in the management of newborns with RDS. The impact of optimal blood pressure, tissue perfusion, and patent ductus arteriosus (PDA) with hemodynamic management in newborns with RDS is going to be reviewed. Also, the short‐ and long‐term outcomes in respect of supportive management of newborns in the intensive care unit will be addressed. We conducted electronic searches of articles on supportive (non‐pulmonary) management and reviewed the consensus guidelines on management of newborns with RDS [1].
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\n
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3. Prenatal care
\n
Every newborn can develop RDS, but the likelihood among the premature infants to be affected with the RDS is the highest [2, 3]. Therefore, as neonatal RDS is a disease predominantly affecting the preterm newborns, all the measures to decrease preterm delivery encompass its management. Preconception advice starting in teenage youth to prevent pregnancy in too young teenage girls is important, and social programs should be developed and delivered among the youths. This is not only the problem in poor countries in the world but is even more problematic in wealthy countries with high‐gross domestic product but also extreme social inequalities. This preconception advice is closely related to proper protection from the sexually transmitted diseases which may also affect the fetal and later newborn\'s life. Both, youth pregnancy and sexually transmitted diseases together with under‐ or malnutrition, strongly affect the development of the fetus and premature delivery. Publically available access to the proper maternity care, at least in well‐developed countries, should be offered to every pregnant woman: adequate number of visits at the obstetrician\'s, appropriate number of obstetric ultrasounds, teaching programs and screening for infections, developmental malformations, etc. Special problems are unwanted pregnancies because any termination of unwanted pregnancy brings different problems to the mother and future wanted pregnancies, but it is worth mentioning that illegal and criminal or nonprofessional abortion endangers the health and lives of the women [4].
\n
In well‐organized health systems, ultrasound measurement of cervical length in midtrimester enables prediction of preterm labor and women with short cervix (<25 mm) should be offered vaginal progesterone treatment [5]. Women with threatening preterm labor should be transferred by “in utero” transport to tertiary level medical centers where better outcomes in regards to mothers and newborns can be provided [6]. In the case of preterm premature rupture of membranes (PPROM), after reassuring maternal and fetal wellbeing threatened preterm delivery can be delayed by antibiotics treatment for 7 days to mothers from about 23 weeks up to 34 weeks of gestation [7]. Antibiotics reduce the rate of chorioamnionitis, preterm birth, infection, and respiratory insufficiency [8]. On the contrary, antibiotics have not been proved beneficial for mothers with preterm labor and intact membranes [9]. Delaying the preterm delivery has been also proved for magnesium sulfate which also has beneficial effects for the brain of the preterm newborn [10]. Preterm labor is efficaciously postponed by tocolytics [11]. Antenatal steroids given to mothers from about 23 weeks up to 34 weeks of gestation decrease the risk of neonatal death, RDS, intraventricular hemorrhage (IVH), and necrotizing enterocolitis (NEC) [12]. Moreover, antenatal steroids given more than 24 h and <7 days before elective cesarean section at term also influence the RDS in the late‐preterm or term newborn [13]. Until further studies are done, one repeated dose of antenatal steroids given a week after the first dose is recommended [14].
\n
Chorioamnionitis describes intrauterine inflammation of maternal and fetal tissues and endangers both, the mother and the newborn. It has been recognized as the major risk factor for preterm birth, prematurity‐associated mortality in morbidity of newborns: the neonatal sepsis, RDS, cystic periventricular leukomalacia (PVL), IVH, and cerebral palsy [15, 16]. Since guidelines for the prevention of perinatal group B streptococcal (GBS) disease have been published, the incidence of early‐onset GBS disease in newborns has dramatically decreased. The mayor prevention key is universal antenatal GBS screening of pregnant women and intrapartum antibiotic prophylaxis (IAP) for women with high‐risk of infection with penicillin, ampicillin, or cefazolin. Adequate IAP is achieved by infusion of antibiotics at least 4 h before delivery [17].
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4. Interhospital, “in utero” transport, and regionalization
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Interhospital air and ground transportation of critically ill neonates, regionalization, organization of “in utero” transportations, and new tertiary perinatal centers, which care for the most at risk premature newborns, have greatly decreased the perinatal mortality rate over the last 30 years all over the world [6]. As an example, we present the results from the Republic of Slovenia where we have greatly decreased the perinatal mortality rate over the last 30 years to a rate of 3.5% for neonates weighing at least 1000 g in 2006. We have organized transportation since 1976, and we have transport “in utero” in two Slovenian perinatal centers since 1985 [18].
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5. Temperature management
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From the neonatal history, we learned that misunderstanding the adverse effects of low body temperature in the premature infants was related to higher mortality rate in hypothermic infants. With understanding the importance of normal body temperature later together with the invention of heated air incubators, the mortality rate dropped as much as twice immediately [19–21]. After birth, the newborn baby is exposed to extrauterine environment with temperature changes in relation to the environmental temperatures which are usually lower than the body temperature. Newborns and especially preterms have increased proportion of body surface in relation to body volume, their body has low‐temperature capacity, and their skin is immature with increased water permeability. They also have low supplies of skin fat. Since oxygen and energy consumption are lowest in the range of thermal neutrality, it is important to keep newborns in those limited ambient temperature ranges to enable them to have their body temperature ranging from 36.5 to 37.5°C. By acknowledging the importance of thermal neutrality, this is one of the most manageable problems of non‐pulmonary management of newborns with RDS [22].
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Temperature regulation enables optimal efficiency of the metabolic processes and enzyme activities with the lowest oxygen and calorie consumption. Newborns are unable to produce sufficient heat by metabolic reactions, by muscle activity during motion, and by nonshivering thermogenesis in the brown fat, which starts to evolve between 26th and 30th weeks of gestation. Loosing heath from the body is modulated by changing the vascular tone of peripheral vessels and by sweating, which is not fully developed by the 36th week of gestation.
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There are four ways newborns may lose heat to the environment. Immediately after birth, they are wet from the amniotic fluid and evaporation decreases their body temperature fast so all the measures to dry their body have to be taken. Recently, to decrease evaporation from the immature water permeable skin, very premature newborns, still wet, are immediately wrapped into plastic wraps or bags and caps [23–27]. To lessen the evaporation, the air in the incubators for all the preterms beyond 31 weeks of gestation should be humidified (60–80%) and preterm newborns should not be bathed until they can maintain their body temperature. The humidity should be decreased by 5% every day if they can maintain stable body temperature, and stopped when preterms can maintain their body temperature in 40% humidity [28]. Every object radiates—it gives or receives the heat in relation to the temperature difference. Therefore, it is important to keep the air temperature in a defined range and also to take into account the external temperatures, the room walls and windows and the isolation walls of the incubators [29]. Objects can lose heat by losing or gaining heat from the object in contact by conduction. Placing the newborn baby to the mother\'s abdomen allows skin to skin contact besides parental bonding and enables conduction of the heat from the mother to the child [22, 30–32]. Resuscitation on wet basis can cause a huge heat loss from the newborn and should be avoided. Infusing cold fluids also causes conduction loss of heat. Moving air causes heat loss by convection.
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Hypothermia may lead to hypoglycemia or acidosis and has been associated with increased mortality, increased risk of late‐onset sepsis, IVH, pulmonary insufficiency, and hemorrhage [20, 21]. The vicious cycle of cooling causes norepinephrine release with pulmonary and peripheral vasoconstriction with increased right‐to‐left shunting of blood and maintenance of fetal circulation postnatally. To enable thermal neutrality, preterm newborns should be nursed in preheated and humidified incubators, and in heated beds after 32nd week of gestation or >1500 g. We provide them heated and humidified gases and clothe newborns with clothes and caps [33, 34].
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6. Perinatal infection management
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After the initial care of the newborn in the delivery room with drying the newborn\'s skin, providing warmth, positioning the head, and clearing the airway, the evaluation of respiration, and consequently oxygenation of peripheral organs follows. In case transitional period is prolonged and the signs of RDS persist, we have to obtain chest radiograph, blood gas analysis and perform sepsis work‐up with complete blood count and cultures and start empirical antibiotic treatment with ampicillin or penicillin and gentamicin, especially if risk factors for early‐onset sepsis are present. Early‐onset infection with GBS typically imitates the RDS in preterm newborns with the clinical presentation and also radiographically so usually it is difficult to differentiate pneumonia from RDS without infection. Besides GBS congenital pneumonia can be caused by Escherichia coli and other microorganisms [35]. A well appearing newborn to a mother with chorioamnionitis should have a limited diagnostic evaluation and receive empirical antibiotic therapy. Well‐appearing term newborns, born to mothers with appropriate IAP or inappropriate IAP with rupture of membranes for <18 h, need routine care and observation. Those term newborns whose mothers had inappropriate IAP and rupture of membranes for more than 18 h and all preterm newborns with inadequate IAP need clinical and laboratory evaluation and observation [17, 36]. There is no evidence to support routine antibiotic treatment of newborns with RDS and without risk factors for early‐onset sepsis [37, 38]. In those newborns with RDS which do not have laboratory signs of sepsis and have negative cultures, the antibiotics should be discontinued as early as feasible [37, 39].
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Late‐onset sepsis occurs in one‐fifth of premature newborns and is associated with increased mortality, prolonged hospitalization, and prolonged artificial ventilation, PDA, NEC, and BPD [40]. Newborns that were treated for neonatal sepsis later are at risk of poor weight gain and adverse neurodevelopmental outcome [41].
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7. Fluid and electrolyte management
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After birth, water and electrolyte balance is influenced by transitional and developmental adaptations of the newborn. More preterm newborns have more total body water, and extracellular fluid volume constitutes a greater part of total body water in comparison with term newborns. Furthermore, after birth, renal function of preterm newborns is reduced in comparison with term newborns and they lose more weight with diuresis which results from an isotonic reduction of extracellular fluid. Newborns, especially more preterm ones loose water insensibly through the skin and respiratory system, especially in RDS, when respiratory rate is increased [42, 43]. Insensible water loss is increased by radiant heaters, phototherapeutic lights, and inappropriate water content of inspired air. Antenatal steroids besides the already mentioned effect on lung maturation also accelerate skin and kidney maturation. Preterm newborns whose mothers have received antenatal steroids had lower insensible water loss, less hypernatremia, earlier diuresis and natriuresis, and less nonoliguric hyperkalemia [44, 45]. In the first postnatal days, water balance is kept in a slightly negative state. Excessive fluid administration is associated with increased risk of PDA, NEC, and BPD [46]. Fluid balance and volume status can be evaluated by physical examination with signs of hydration, edema, and hemodynamic stability, body weight loss or gain, balance of fluid intake and output, and biochemistry evaluation of electrolyte concentration in plasma of the newborns. Fluid requirements therefore account for maintenance requirements, obligatory losses, and possible deficits and are gestational and postnatal age, ambient temperature and humidity, renal and respiratory function dependent. The electrolyte requirements for sodium, potassium, and chloride are approximately 1–2 mEq/kg/day except for the first day when isotonic reduction of extracellular fluid ensues. Diuretics cause electrolyte disturbances due to urinary loss of sodium and potassium and loop diuretics are associated with nephrocalcinosis so we prefer not to use them routinely [47].
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8. Nutritional management
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The newborn\'s nutritional status is influenced by his past history with genetic background, maternal body composition, and nutrition before and during pregnancy [48]. Many preterm newborns are born growth restricted because of inadequate intrauterine nutrient supply. Postnatal nutrition and metabolic capacity impact postnatal growth and development and have long‐term consequences on the lung, brain, and other organ development and cognitive function [49]. The newborn’s brain consumes half of all the energy provided, and too little calories mean less brain volume and worse neurocognitive outcome. Adequate volume of fluids, the protein content, and energy balance in the newborn’s, and especially preterm’s nutrition should cover metabolic expenditure and growth requirements, thus setting the ground for optimal outcomes.
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In newborns with RDS, early enteral feeding is frequently delayed because of concomitant medical problems and fear of complications as the feeding intolerance and NEC. Therefore, the parenteral nutrition is commenced as early as possible to correct prenatal, to prevent postnatal growth failure and to improve outcomes [50, 51]. The parenteral nutrition has to provide enough calories for energy and growth, which are met by carbohydrates, proteins, and lipids. Carbohydrates provide glucose, proteins provide essential amino acids and nitrogen, and lipids provide essential fatty acids. Essential nutrients needed for growth are electrolytes, vitamins, minerals, and trace elements [52–54].
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The premature newborn needs parenterally about 100 kcal/kg/day of nonprotein energy for growing, 3/5 in the form of carbohydrates and 2/5 in the form of lipids. Glucose is the form of carbohydrates that we give parenterally, and it is the primary energy supply for the newborn\'s brain. We start with 7 g/kg/day of glucose, which provides 4.8 mg/kg/min of glucose, and we increase the amount by 1.5–2 g/kg/day, up to 15 g/kg/day and maximum of 18 g/kg/day (12.5 mg/kg/min). Preterm newborns are prone to hypoglycemia because of higher glucose needs, decreased fat stores, and higher‐energy consumption. On the other hand, for many metabolic and nutritional reasons, they are also prone to hyperglycemia. As early as feasible, we start with 2 g/kg/day of proteins and increase the amount by 0.5–1 to 3.5–4 g/kg/day of proteins, which is needed to attain the intrauterine growth rate [55, 56]. It is also important to provide the preterm 25 nonprotein kcal/1 g of proteins. Low blood urea nitrogen (BUN) is a sign of inadequate protein intake, but a high BUN does not correlate well with a high protein intake [57]. A preterm newborn daily loses 1 g of proteins through the kidneys, and a good caloric input with appropriately balanced diet accumulates 2 g of proteins. Thus, improperly balanced nutrition of a newborn can lead to a loss of 15% of protein mass in 2 days [58]. There are eight essential amino acids in parenteral nutrition and six more for the preterm newborn. Adding cysteine to the parenteral nutrition improved nitrogen balance [59], but the addition of glutamine had no clinical impact [60]. Concomitantly with proteins, we administer 20% of intravenous lipids, including essential fatty acids and long‐chain n–3 polyunsaturated fatty acids and start with 1 g/kg/day and increase by 0.5 g/kg/day to a maximum of 3–4 g/kg/day [61–63]. Already 0.5 g/kg/day may provide prevention of essential fatty acid deficiency, and the tolerance is guided by triglyceride level of <200 mg/dL. The tolerance is better achieved with the use of continuous infusion of intravenous lipids over 24 h rather than intermittent dosing [64].
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To maintain bone health, the newborns need 1.5–2 mmol/kg/day of calcium and the same amount of phosphorus, and 0.18–0.3 mmol/kg/day of magnesium. The optimal weight ratio of calcium and phosphorus is 1.3–1.7:1. Pediatric vitamin formulations of water‐ and fat‐soluble vitamins and trace elements are in use, but they do not provide enough amounts of vitamin A, D and E so we add them enterally if feasible. Vitamin A affects normal eye and lung development, immunity, and cell differentiation. Supplementation of vitamin A in preterm newborns was associated with reduced risk of oxygen requirement [65]. Selenium supplementation prevented short‐term morbidity in preterm newborns [66]. Although carnitine supplementation was not associated with weight gain or apnea reduction [67, 68] there are recommendations to add parenteral carnitine to preterm newborns needing parenteral nutrition for more than 2 weeks [69]. Nutritional status can be evaluated by anthropometry, body composition and biochemistry, clinical assessment and quantity, and quality dietary evaluation. Adverse effects of parenteral nutrition include line infection and sepsis, extravasation of parenteral fluid, cholestasis, and bone disease.
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To correct the intrauterine growth restriction and achieve appropriate postnatal weight gain, the enteral feeding is also of great significance [70]. It is important to start enteral feeding as early as feasible; in very low birth weight (VLBW) newborns 10–20 mL/kg/day is started in the first 2–5 days, in low birth weight (LBW) newborns in first days [71]. Colostrum acts as the immune therapy for the newborn\'s intestine. Feeding newborns with minimal volumes of milk is known as trophic feeding, which has many beneficial effects for further feeding, increased hormone secretion, motility, and decreased permeability of the gastrointestinal tract [72]. After a few days of gastrointestinal priming, feedings are increased by 10–20 mL/kg/day. Human milk in comparison with formula resulted in earlier adequate energy intake [73, 74]. Fast advancement of milk volume has no adverse outcome in comparison with slow advancement [71]. Feeding every two hours was superior to feeding every three hours in regards to the time to reach full enteral feeds and better weight gain [75]. Tube feeding can be bolus or continuous and neither is superior [76]. Feeding intolerance can be determined by emesis, gastric residuals, distended, and tender abdomen with changed bowel sounds and stool output, but most of them have little prognostic value [77–80]. The prokinetic erythromycin has not been shown to be effective [81–83]. When the newborn tolerates 100 mL/kg/day or has been consuming mother\'s milk for 1 week, formula or mother\'s milk is fortified. The goal of enteral feeding of the preterm newborn is to gain more than 15 g/kg/day.
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9. Pain management
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Critically ill newborn is confronted with different, more or less painful procedures every day in the NICU. Not every procedure is painful, but the usual response from the newborn is typical—removal of the affected part of the body and crying. The more severe the pain, the more distressful situation is for the newborn. Brain not yet fully developed may receive too many painful stimulations per day, and the tinny newborn may overreact even if the next stimulus is less or even not painful. Newborn Individualized Developmental Care and Assessment Program (NIDCAP) is a method of ensuring an adequate physical environment, reducing overwhelming sensory stimulations, and increasing sensitive parent caregiving, for proper brain growth and development of preterm newborns. Despite non‐convincing evidence that NIDCAP improves long‐term neurodevelopmental or short‐term medical outcome, there is a need for high‐quality researches using different techniques to diminish high environmental stress on the premature infants during their treatment in the NICU [84].
\n
Newborns with RDS experience different kinds of pain depending on their morbidities: skin breaking procedures and tissue injury provoke acute or physiological pain, surgery, localized inflammation, and birth trauma cause established pain and diseases like NEC, meningitis, and scalded skin syndrome give rise to prolonged or chronic pain [85]. It has been estimated that sick newborns experience 12–16 procedures each day which are increasingly painful:\n
Management of pain in newborns with RDS encompasses prevention with first awareness of causing pain with different painful procedures and reduction of painful management of the newborn. The second line includes objective assessment for the detection of pain in each neonate. Thirdly, controlling the pain includes cooperation with parents to diminish pain experience, delivering proper analgesia before expected painful medical care and combining nonpharmacological interventions and pharmacological therapy [88–90].
\n
An important issue in caring for a newborn with RDS is minimal handling or “do not touch” approach. This also enables us to take in mind the possible pain we are going to cause to the newborn with our intended handling and executed procedures. On the other hand, we have to carefully plan the management not to compromise the well‐being of the newborn by not performing vital examinations and investigations. By planning the handling of the newborn in limited number of sessions per day, it is possible to disrupt the newborns less times and perform the examinations, nursing care, and blood withdrawal at the same time. We should use laboratory equipment that enables us to analyze several different chemical substances from one small blood sample to reduce the volume of blood taken from the child and avoid iatrogenic anemia. All sick newborns with RDS need intravenous line for fluid, nutritional, antimicrobial, blood pressure, and pain management so a central venous line as soon as possible and for newborns who need several blood investigations per day an artery line should be placed both with appropriate analgesia. With minimally invasive approach, we can gain many data on the well‐being of the newborn by noninvasive monitoring with the use of transcutaneous measuring of the oxygen saturation in peripheral arteries and in different organs by the use of near-infrared spectroscopy (NIRS), partial pressures of oxygen, and carbon dioxide in skin capillaries or bilirubin concentrations [85, 89, 91].
\n
For the assessment of pain, different observational scales designed for special newborn population are in use, which encompass many physiological and behavioral variables. Especially with observation of behavior, there is much subjectivity in the assessment procedure. The available assessment scales have proved usable in acute pain, but there is limited applicability of the assessment scales for assessing prolonged pain, pain in extremely low birth weight (ELBW) newborns and in those receiving paralytic agents [85].
\n
First step on the ladder of pain management constitutes the nonpharmacological measures which include sweet peroral solutions, breastfeeding, sucking, skin‐to‐skin contact, and swaddling with facilitated tucking and sensorial saturation [92]. Combined use of nonpharmacological measures act synergistically [93–95]. Furthermore, when used with pharmacological measures, the pharmacologic use is lesser in frequency and dosage [88, 96]. Sucrose and glucose used before skin‐breaking procedures reduced total crying time, lessened changes of physiological variables, and facial expressions and pain scores of multidimensional pain assessment scales [97, 98]. Currently, it is not entirely clear how sweet solutions suppress the responses to painful stimulation; do they only diminish the response to pain or they really influence the pain perception. With repeated dosing, there is a concern on neurodevelopmental outcome in the preterm newborns [99]. Sucrose alone is used for minor procedures, and combined with other analgesics for moderately painful procedures [97]. In cases when physically possible, breastfeeding or mother\'s milk is at least as effective as sweet solutions [100]. Further on, engaging different body sensors with sensations, like non‐nutritive sucking, swaddling, facilitated tucking, rocking, holding, kangaroo care and sensorial saturation, gives the brain other stimuli and therefore the brain has closed door for pain reception [88, 92].
\n
Topical analgesia with the use of Eutectic Mixture of Local Anesthetics (EMLA) or lidocaine alone are used with effect in venous, arterial, and lumbar punctures and also venous, arterial catheter placement, and circumcision. With reasonable dosing, methemoglobinemia is not a significant problem [101].
\n
Systemic analgesia can be provided by nonopioid, nonsteroidal anti‐inflammatory agents, opioid analgesics, and sedatives. Paracetamol (acetaminophen) does not diminish pain perception after assisted vaginal birth, heel lance, or eye examination. Paracetamol may diminish the need for morphine after surgical procedures in newborns [102]. We use nonsteroidal anti‐inflammatory agents for closing PDA in preterm newborns, but because of their serious adverse effects, like gastrointestinal bleeding, platelet dysfunction and decreased glomerular filtration rate, we do not use them as analgesics in newborns. The most powerful analgesics are opioids, and morphine is the most frequently used, either intermittently for acute pain with invasive procedures or continuously for established pain during artificial ventilation or after surgery. Morphine reduces acute pain after some invasive procedures: central line, tracheal, and chest tube insertion [103, 104], but not heelstick [105] or tracheal suctioning [106, 107]. The NEOPAIN study showed no difference in mortality rate, severe IVH and PVL between ventilated preterm newborns receiving continuous morphine or placebo. The preterm newborns treated with morphine had less pain, but more hypotension, longer duration of artificial ventilation and longer time to full volume feeds [103]. Morphine is safe and effective for treating established pain after surgery in newborns [108, 109]. In extremely preterm newborns, opioid analgesics should be used cautiously [110, 111].
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More rapid analgesia with fewer hemodynamic adverse effects is achieved by fentanyl and shorter‐acting derivatives, which is suitable for acute invasive procedures in controlled clinical setting like tracheal tube and central line placement [112, 113]. There was no favorable effect on established pain during artificial ventilation of premature newborns using fentanyl [114]. Furthermore, premature newborns treated with continuous fentanyl had prolonged time of artificial ventilation and of meconium passage. Fentanyl is used for treating established pain after surgery and in newborns with pulmonary hypertension.
\n
Ketamine causes analgesia with sedation and amnesia with no effect on respiration and increasing blood pressure and heart rate [115]. It is used in newborns with hemodynamic instability for acute pain with invasive procedures and for established pain during and after surgery [116]. Among sedatives midazolam which can cause prolonged sedation in sick preterm newborns is not recommended for use in preterm newborns [117].
\n
Painful experiences in early childhood may have unfavorable consequences for neurodevelopment [118, 119]. Although there are some data indicating that prolonged use of analgesics in newborns does not influence long‐term neurodevelopmental and behavioral outcome [120–122], more recent studies have shown some adverse long‐term effects on growth, neurological, and behavioral outcome [123]. A positive autonomic nervous system\'s stability to pain in neonates with kangaroo care or skin to skin care can be proved by measuring heart rate variability [124, 125].
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\n
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10. Blood pressure and perfusion management
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Systemic blood pressure is dependent on systemic blood flow with cardiac output and systemic vascular resistance. Hypotension ensues in cases of decreased cardiac output as a result of cardiac dysfunction or hypovolemia with inadequate compensation with vasomotor tone, or, decreased vasomotor tone with inadequate compensatory increase in cardiac output. Hypotension, especially in preterms, is difficult to define unequivocally; population‐based normative blood pressure data show the increment of blood pressure with increasing gestational and postnatal age, but normal gestational and postnatal age dependent blood pressure range is not known [126]. The physiological principles of blood pressure define autoregulatory threshold where there is loss of autoregulation of blood flow to vital organs, functional threshold where there is loss of cellular function, and ischemic threshold where there is loss of functional integrity [127]. Blood pressure correlates poorly with systemic and cerebral blood flow; therefore, different measurement approaches combined with clinical assessment of adequate perfusion have been investigated for the purpose of better hemodynamic monitoring. Systemic blood flow can be measured by clinician performed ultrasound of the heart and blood vessels with the pressure wave‐form analysis and by magnetic resonance imaging (MRI) [128, 129]. Systemic resistance is evaluated by Laser‐Doppler technique and by NIRS [130]. Noninvasively, NIRS gives us information about oxygenation of organs, inferring about oxygen delivery, and oxygen demand of certain tissues. The brain activity can continuously be monitored by concomitant use of NIRS and amplitude integrated electroencephalography (EEG) [131, 132].
\n
The blood flow is regulated by cardiac output, carbon dioxide tension, local neuronal and chemical activity, changes in cerebrospinal fluid hydrogen ion concentration, arterial oxygen content, hemoglobin, and blood glucose [133–135]. Accordingly, systemic blood flow can be improved by inotropes or volume, and systemic resistance can be improved by vasopressors and lusitropes. Treatment of neonatal hypotension improves blood pressure, cardiac output, organ blood flow, lactic acidosis, peripheral perfusion, and urine output. Neonatal hypotension endangers cerebral autoregulation and increases morbidity and mortality in preterm newborns [136, 137].
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Low systemic blood pressure frequently occurs in the early stages of RDS. Therefore, blood pressure should frequently be measured, either noninvasively or invasively with intravascular line. For volume expansion, after hypovolemia crystalloid or colloid solutions are used [138, 139]. For decreased cardiac output because of cardiac dysfunction, the initial agent is dopamine, later dobutamine, and epinephrine are added [140, 141]. In newborns with refractory hypotension or high‐dose inotropic therapy, glucocorticoid therapy increases blood pressure [142, 143]. Different developmental factors affect hemodynamic response to sympathomimetic amines in newborns [144]. Before deciding on a specific therapy of hypotension, potentially reversible causes have to be taken in mind and corrected if possible (measurement error, blood loss, pneumothorax, sepsis, adrenocortical insufficiency).
\n
There is conflicting evidence on the management of hypotension improving clinically meaningful longer‐term outcome measures in VLBW newborns, but there are many confounding factors influencing the outcome of management of preterm newborns and studies are weak to show the impact [145–148].
\n
Besides cardiac output, the oxygen supply to the tissues depends also on the content of oxygen in the arteries, which is in the biggest part a function of concentration of hemoglobin. Target values of hemoglobin or hematocrit differ with regards to the gestational and postnatal age of the newborn, the rate of evolution of anemia, the presence of clinical signs of anemia, and the degree of respiratory support [149]. Targeting to lower concentrations of hemoglobin in ELBW newborns might have no effect on short‐term outcomes, but may have a negative impact on the longer‐tem neurodevelopmental outcome [150, 151]. Anemia can be avoided or postponed by delayed cord clamping or cord milking and also by applications of erythropoietin. Delayed cord clamping and cord milking in preterm newborns was associated with higher hematocrit, fewer transfusions, less IVH, NEC, and no increased need for phototherapy because of jaundice [152–156]. Also, preterm newborns who were receiving erythropoietin received fewer transfusions and had higher cognitive scores at 18–22 months of corrected age [157, 158].
\n
\n
\n
11. PDA management
\n
Shunting blood from the aorta to the pulmonary artery means decreased blood flow in the systemic circulation and low perfusion of peripheral organs and increased blood flow in the pulmonary circulation with RDS, pulmonary edema, BPD, IVH, NEC, and heart failure. Newborns with PDA have higher mortality rate and increased risk of pulmonary edema, hemorrhage, and BPD. The field of management of the PDA is an area in neonatal practice which has, perhaps, changed the most in the last decades and many questions still remain unanswered. The uses of antenatal steroids, postnatal surfactant, and the gentler modes of ventilation with lower oxygen saturation targets may have lowered the incidence and the impact of clinically significant PDA shunt. In VLBV newborns with RDS, PDA is present in 30% [159, 160]. Current management of the PDA generally includes three approaches. Supportive care for newborns with PDA encompasses providing thermal neutrality, using PEEP, keeping hematocrit between 35 and 40%, fluid restriction of 110–130 ml/kg/day, permissive hypercapnia, low oxygen saturation targets and, in case of diuretic need, thiazide diuretics over loop diuretics. If the newborn has poor perfusion, a large left‐to‐right shunt and remains artificially ventilated for a longer time a course of cyclooxygenase (COX) inhibitors is administered, favoring ibuprofen over indomethacin, because the latter is reducing blood flow to the brain, gastrointestinal tract, and kidneys [161, 162]. Ibuprofen is efficacious for closing PDA given either intravenously or orally [163]. Newborns, who remain artificially ventilated and have failed to respond to COX inhibitor, are candidates for surgical ligation, which has been associated with adverse long‐term outcomes [164].
\n
The prophylactic therapy to reduce the incidence of PDA has not been proved to be of benefit. The prophylactic indomethacin has been shown to have no impact on mortality, neurologic impairment, BPD, or NEC although it was associated with reduction of hemodynamically important PDA and severe IVH [165]. The prophylactic ibuprofen has been linked with adverse effects [166, 167].
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12. Postnatal supplemental management of respiratory support
\n
Apnea of prematurity is a developmental consequence of immature respiratory center in premature newborns. Besides mechanical ventilation with oxygen supplementation the management of apnea of prematurity encompasses supportive measures like assuring the temperature stability, proper positioning of the newborn\'s head and neck and ensuring the nasal patency. Methylxanthines stimulate the respiratory drive by increasing the responsiveness of respiratory center to carbon dioxide and decreasing its hypoxic depression. The medicines also have inotropic effects on respiratory muscles [168]. Caffeine is being preferred over theophylline and other agents [169]. Caffeine therapy has been proved to shorten the duration of mechanical ventilation and supplemental oxygen and also reducing the risk of BPD and PDA ligation [170, 171]. The same effects have been shown for prophylactic use of caffeine in very preterm newborns [172, 173]. There have been some positive neurodevelopmental effects of caffeine therapy proved during follow‐up of children treated with caffeine during neonatal period [174–176].
\n
The duration of mechanical ventilation can be shortened and the risk of BPD diminished by the use of postnatal tapering course of low‐ (<0.2 mg/kg/day) or even very low‐dose dexamethasone (0.05 mg/kg/day) [177, 178]. Hydrocortisone has been proved to have the same beneficial effects on earlier extubating of mechanically ventilated preterm newborns [179].
\n
\n
\n
13. Conclusion
\n
For the best outcomes of newborns with RDS, besides optimal pulmonary management, it is of extreme importance to have optimal supportive care (Table 1) starting prenatally and aiming at newborns being delivered in highly specialized tertiary centers with timing of birth after completion of a course of prenatal steroids. Body temperature should be maintained between 36.5 and 37.5°C. Preterm newborns should be nursed in incubators with high relative humidity (60–80%) and started on intravenous fluids of 70–80 ml/kg/day, later managed individually, based on weight change and serum electrolyte concentrations. Both parenteral and minimal enteral nutrition should be started as early as possible—from day 1—and quickly increased to 3.5 g/kg/day of proteins and 3 g/kg/day of lipids. Proper infection control starts prenatally with administering antibiotics to women with preterm prelabor rupture of membranes, and before labor to those with risk factors for early‐onset sepsis. Furthermore, antibiotics are given to newborns with RDS until early‐onset sepsis is ruled out. Adequate treatment of pain may be associated with decreased complications and mortality. Sedatives do not provide pain relief and may mask newborn\'s response to pain. Additionally, proper management of the PDA and hemodynamic support of the circulation with good systemic perfusion and oxygenation are also of utmost importance for the best outcomes of newborns with RDS.
\n
\n
\n
Prenatal care
\n
All the measures to prevent preterm delivery should be taken (counseling, progesterone, antibiotic, magnesium sulfate, tocolysis) If possible, birth should be delayed to allow effect of antenatal steroid therapy to the mother Timely and safe transport of the expectant mother to specialized tertiary centers Appropriate intrapartum antibiotic prophylaxis
\n
\n
\n
Delivery room stabilization
\n
Delayed cord clamping or cord milking at birth Collecting cord blood for diagnostic purposes (hemogram, hemoculture, blood group, virology) Stabilization of the preterm newborn in a plastic bag under a radiant warmer Drying the newborn\'s skin, providing warmth, positioning the head and clearing the airway, evaluation of respiration and oxygenation of peripheral organs
\n
\n
\n
Supportive care
\n
Nursing the newborn in incubators with heated and humidified air In cases with risk factors for early-onset sepsis and/or clinical and laboratory signs of sepsis antibiotics should be started Insertion of central lines to enable blood withdrawal for diagnostic purposes and parenteral nutrition Careful fluid and electrolyte therapy Early parenteral nutrition and early trophic feeding Minimal handling with clustered care of examination, blood withdrawal and nursing care at the same time but not to overburden the neonate Regular use of appropriate pain assessment scales and proper analgesia before planned procedures Regular measurement of blood pressure and assessment of peripheral perfusion to decide on possible hemodynamic therapy Targeting hemoglobin or hematocrit values in regards to the gestational and postnatal age, the rate of evolution of anemia, the presence of clinical signs of anemia and the degree of respiratory support needed Consideration on the presence and clinical significance of patent ductus arteriosus to decide on possible therapies Caffeine therapy to minimize the need for and duration of ventilation Consideration on postnatal tapering course of low- or very low-dose dexamethasone or hydrocortisone
\n
\n\n
Table 1.
Summary of recommendations for non-pulmonary management of newborns with respiratory distress.
\n\n',keywords:"newborns, evidence‐based therapy, antenatal steroids, transport in utero, regionalization of maternity hospitals and neonatal intensive care units, thermoregulation, fluid, nutrition, antibiotics, pain, blood pressure, perfusion, patent ductus arteriosus",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/50701.pdf",chapterXML:"https://mts.intechopen.com/source/xml/50701.xml",downloadPdfUrl:"/chapter/pdf-download/50701",previewPdfUrl:"/chapter/pdf-preview/50701",totalDownloads:1203,totalViews:199,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,dateSubmitted:"October 28th 2015",dateReviewed:"March 30th 2016",datePrePublished:null,datePublished:"August 31st 2016",dateFinished:"May 12th 2016",readingETA:"0",abstract:"Due to the developmental immaturity of the lungs and other organs, the premature newborns are more prone to develop respiratory distress syndrome (RDS) and other problems of prematurity. The prevention of heat and water loses improves survival. Intolerance to excessive fluids and electrolytes in the transitional period may affect urine and sodium excretion together with maladaptation of cardiovascular system, the development of heart failure, and deterioration of RDS due to patent ductus arteriosus (PDA) and further development of bronchopulmonary dysplasia (BPD). Closure of PDA is frequently needed. The “trophic feeding” and intensive nutrition as soon as possible prevent weight loss and further growth restriction. Greater sensitivity to pain, short‐ and long‐term effects of inappropriately treated pain, use of opioids and sedatives are of concern in the short‐ and long‐term outcomes. Cardiovascular stability and adequate perfusion of the brain both affect the neurological outcome. Delayed cord clamping and erythropoietin help maintaining adequate levels of circulating hemoglobin which might affect later cognitive outcomes. In the following sections, detailed descriptions of non‐pulmonary management will be presented. We conducted electronic searches of articles on supportive (non‐pulmonary) management of newborns with RDS. Consensus guidelines on newborns with respiratory distress have been reviewed.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/50701",risUrl:"/chapter/ris/50701",book:{slug:"respiratory-management-of-newborns"},signatures:"Petja Fister and Štefan Grosek",authors:[{id:"180648",title:"Associate Prof.",name:"Petja",middleName:null,surname:"Fister",fullName:"Petja Fister",slug:"petja-fister",email:"petja_fister@yahoo.com",position:null,institution:{name:"University of Ljubljana",institutionURL:null,country:{name:"Slovenia"}}},{id:"185445",title:"Prof.",name:"Štefan",middleName:null,surname:"Grosek",fullName:"Štefan Grosek",slug:"stefan-grosek",email:"stefan.grosek@kclj.si",position:null,institution:{name:"University of Ljubljana",institutionURL:null,country:{name:"Slovenia"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Methods",level:"1"},{id:"sec_3",title:"3. Prenatal care",level:"1"},{id:"sec_4",title:"4. Interhospital, “in utero” transport, and regionalization",level:"1"},{id:"sec_5",title:"5. Temperature management",level:"1"},{id:"sec_6",title:"6. Perinatal infection management",level:"1"},{id:"sec_7",title:"7. Fluid and electrolyte management",level:"1"},{id:"sec_8",title:"8. Nutritional management",level:"1"},{id:"sec_9",title:"9. Pain management",level:"1"},{id:"sec_10",title:"10. Blood pressure and perfusion management",level:"1"},{id:"sec_11",title:"11. PDA management",level:"1"},{id:"sec_12",title:"12. Postnatal supplemental management of respiratory support",level:"1"},{id:"sec_13",title:"13. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'Sweet DG, Carnielli V, Greisen G, Hallman M, Ozek E, Plavka R, et al. European consensus guidelines on the management of neonatal respiratory distress syndrome in preterm infants—2013 update. 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Doi:10.1542/peds.2012‐2779.'},{id:"B147",body:'Batton B, Zhu X, Fanaroff J, Kirchner HL, Berlin S, Wilson‐Costello D, et al. Blood pressure, anti‐hypotensive therapy, and neurodevelopment in extremely preterm infants. J Pediatr. 2009;154(3):351–7, 7.e1. doi:10.1016/j.jpeds.2008.09.017.'},{id:"B148",body:'Logan JW, ‘O\'Shea TM, Allred EN, Laughon MM, Bose CL, Dammann O, et al. Early postnatal hypotension and developmental delay at 24 months of age among extremely low gestational age newborns. Arch Dis Child Fetal Neonatal Ed. 2011;96(5):F321–8. Doi:10.1136/adc.2010.183335.'},{id:"B149",body:'Bishara N, Ohls RK. Current controversies in the management of the anemia of prematurity. Semin Perinatol. 2009;33(1):29–34. Doi:10.1053/j.semperi.2008.10.006.'},{id:"B150",body:'Whyte RK. Neurodevelopmental outcome of extremely low‐birth‐weight infants randomly assigned to restrictive or liberal hemoglobin thresholds for blood transfusion. Semin Perinatol. 2012;36(4):290–3. Doi:10.1053/j.semperi.2012.04.010.'},{id:"B151",body:'Kirpalani H, Whyte RK, Andersen C, Asztalos EV, Heddle N, Blajchman MA, et al. The Premature Infants in Need of Transfusion (PINT) study: a randomized, controlled trial of a restrictive (low) versus liberal (high) transfusion threshold for extremely low birth weight infants. J Pediatr. 2006;149(3):301–7.'},{id:"B152",body:'Backes CH, Rivera BK, Haque U, Bridge JA, Smith CV, Hutchon DJ, et al. Placental transfusion strategies in very preterm neonates: a systematic review and meta‐analysis. Obstet Gynecol. 2014;124(1):47–56. Doi:10.1097/AOG.0000000000000324.'},{id:"B153",body:'Committee on Obstetric Practice, American College of Obstetricians and Gynecologists. Committee Opinion No.543: Timing of umbilical cord clamping after birth. Obstet Gynecol. 2012;120(6):1522–6. Doi:10.1097/01.AOG.0000423817.47165.48.'},{id:"B154",body:'Rabe H, Diaz‐Rossello JL, Duley L, Dowswell T. 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Doi:10.1002/14651858.CD004868.pub4.'},{id:"B158",body:'Ohls RK, Kamath‐Rayne BD, Christensen RD, Wiedmeier SE, Rosenberg A, Fuller J, et al. Cognitive outcomes of preterm infants randomized to darbepoetin, erythropoietin, or placebo. Pediatrics. 2014;133(6):1023–30. Doi:10.1542/peds.2013‐4307.'},{id:"B159",body:'Benitz WE, Committee on Fetus and Newborn. Patent ductus arteriosus in preterm infants. Pediatrics. 2016;137(1):1–6. Doi:10.1542/peds.2015‐3730.'},{id:"B160",body:'Fanaroff AA, Stoll BJ, Wright LL, Carlo WA, Ehrenkranz RA, Stark AR, et al. Trends in neonatal morbidity and mortality for very low birthweight infants. Am J Obstet Gynecol. 2007;196(2):147.e1–8.'},{id:"B161",body:'Ohlsson A, Walia R, Shah SS. Ibuprofen for the treatment of patent ductus arteriosus in preterm or low birth weight (or both) infants. Cochrane Database Syst Rev. 2015;2:CD003481. Doi:10.1002/14651858.CD003481.pub6.'},{id:"B162",body:'Herrera C, Holberton J, Davis P. Prolonged versus short course of indomethacin for the treatment of patent ductus arteriosus in preterm infants. Cochrane Database Syst Rev. 2007;(2):CD003480.'},{id:"B163",body:'Neumann R, Schulzke SM, Bührer C. Oral ibuprofen versus intravenous ibuprofen or intravenous indomethacin for the treatment of patent ductus arteriosus in preterm infants: a systematic review and meta‐analysis. Neonatology. 2012;102(1):9–15. Doi:10.1159/000335332.'},{id:"B164",body:'Malviya MN, Ohlsson A, Shah SS. Surgical versus medical treatment with cyclooxygenase inhibitors for symptomatic patent ductus arteriosus in preterm infants. Cochrane Database Syst Rev. 2013;3:CD003951. Doi:10.1002/14651858.CD003951.pub3.'},{id:"B165",body:'Fowlie PW, Davis PG, McGuire W. Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants. Cochrane Database Syst Rev. 2010;(7):CD000174. Doi:10.1002/14651858.CD000174.pub2.'},{id:"B166",body:'Gournay V, Roze JC, Kuster A, Daoud P, Cambonie G, Hascoet JM, et al. Prophylactic ibuprofen versus placebo in very premature infants: a randomised, double‐blind, placebo‐controlled trial. Lancet. 2004;364(9449):1939–44.'},{id:"B167",body:'Van Overmeire B, Allegaert K, Casaer A, Debauche C, Decaluwé W, Jespers A, et al. Prophylactic ibuprofen in premature infants: a multicentre, randomised, double‐blind, placebo‐controlled trial. Lancet. 2004;364(9449):1945–9.'},{id:"B168",body:'Abu‐Shaweesh JM, Martin RJ. Neonatal apnea: ‘what\'s new? Pediatr Pulmonol. 2008;43(10):937–44. Doi:10.1002/ppul.20832.'},{id:"B169",body:'Eichenwald EC, Committee on Fetus and Newborn. Apnea of prematurity. Pediatrics. 2016;137(1):1–7. Doi:10.1542/peds.2015‐3757.'},{id:"B170",body:'Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, et al. Caffeine therapy for apnea of prematurity. N Engl J Med. 2006;354(20):2112–21.'},{id:"B171",body:'Davis PG, Schmidt B, Roberts RS, Doyle LW, Asztalos E, Haslam R, et al. Caffeine for apnea of prematurity trial: benefits may vary in subgroups. J Pediatr. 2010;156(3):382–7. Doi:10.1016/j.jpeds.2009.09.069.'},{id:"B172",body:'Lodha A, Seshia M, McMillan DD, Barrington K, Yang J, Lee SK, et al. Association of early caffeine administration and neonatal outcomes in very preterm neonates. JAMA Pediatr. 2015;169(1):33–8. Doi:10.1001/jamapediatrics.2014.2223.'},{id:"B173",body:'Henderson‐Smart DJ, Davis PG. Prophylactic methylxanthines for endotracheal extubation in preterm infants. Cochrane Database Syst Rev. 2010;(12):CD000139. Doi:10.1002/14651858.CD000139.pub2.'},{id:"B174",body:'Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, et al. Long‐term effects of caffeine therapy for apnea of prematurity. N Engl J Med. 2007;357(19):1893–902.'},{id:"B175",body:'Schmidt B, Anderson PJ, Doyle LW, Dewey D, Grunau RE, Asztalos EV, et al. Survival without disability to age 5 years after neonatal caffeine therapy for apnea of prematurity. JAMA. 2012;307(3):275–82. Doi:10.1001/jama.2011.2024.'},{id:"B176",body:'Doyle LW, Schmidt B, Anderson PJ, Davis PG, Moddemann D, Grunau RE, et al. Reduction in developmental coordination disorder with neonatal caffeine therapy. J Pediatr. 2014;165(2):356–9.e2. doi:10.1016/j.jpeds.2014.04.016.'},{id:"B177",body:'Watterberg KL, American Academy of Pediatrics. Committee on Fetus and Newborn. Policy statement—postnatal corticosteroids to prevent or treat bronchopulmonary dysplasia. Pediatrics. 2010;126(4):800–8. Doi:10.1542/peds.2010‐1534.'},{id:"B178",body:'Tanney K, Davis J, Halliday HL, Sweet DG. Extremely low‐dose dexamethasone to facilitate extubation in mechanically ventilated preterm babies. Neonatology. 2011;100(3):285–9. Doi:10.1159/000326273.'},{id:"B179",body:'Hitzert MM, Benders MJ, Roescher AM, van Bel F, de Vries LS, Bos AF. Hydrocortisone vs. dexamethasone treatment for bronchopulmonary dysplasia and their effects on general movements in preterm infants. Pediatr Res. 2012;71(1):100–6. Doi:10.1038/pr.2011.15.'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Petja Fister",address:"petja.fister@kclj.si and petja_fister@yahoo.com",affiliation:'
Department of Neonatology, University Children’s Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia
Department of Pediatric Surgery and Intensive Therapy, Surgical Service, University Medical Centre Ljubljana, Ljubljana, Slovenia
Department of Pediatrics, Medical Faculty, University of Ljubljana, Ljubljana, Slovenia
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Tomich, Urška Bukovnik, Jammie Layman and Bruce D. Schultz",authors:[{id:"79549",title:"Prof.",name:"John M.",middleName:null,surname:"Tomich",fullName:"John M. Tomich",slug:"john-m.-tomich"}]},{id:"34288",title:"Improving Cell Surface Functional Expression of Delta F508 CFTR: A Quest for Therapeutic Targets",slug:"improving-cell-surface-functional-expression-of-deltaf508-cftr-a-quest-for-therapeutic-targets",signatures:"Yifei Fan, Yeshavanth K. 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Said",authors:[{id:"84459",title:"Prof.",name:"Valerie",middleName:null,surname:"Chappe",fullName:"Valerie Chappe",slug:"valerie-chappe"},{id:"91057",title:"Prof.",name:"Sami",middleName:null,surname:"Said",fullName:"Sami Said",slug:"sami-said"}]},{id:"34292",title:"Pharmacological Potential of PDE5 Inhibitors for the Treatment of Cystic Fibrosis",slug:"pharmacological-potential-of-pde5-inhibitors-for-the-treatment-of-cystic-fibrosis",signatures:"Bob Lubamba, Barbara Dhooghe, Sabrina Noël and Teresinha Leal",authors:[{id:"88540",title:"Prof.",name:"Teresinha",middleName:null,surname:"Leal",fullName:"Teresinha Leal",slug:"teresinha-leal"},{id:"129673",title:"Dr.",name:"Bob",middleName:"Arthur",surname:"Lubamba",fullName:"Bob Lubamba",slug:"bob-lubamba"}]},{id:"34293",title:"Pharmacological Modulators of Sphingolipid Metabolism for the Treatment of Cystic Fibrosis Lung Inflammation",slug:"pharmacological-modulators-of-sphingolipid-metabolism-for-the-treatment-of-cystic-fibrosis-lung-infl",signatures:"M.C. Dechecchi, E. Nicolis, P. Mazzi, M. Paroni, F. Cioffi, A. Tamanini,V. Bezzerri, M. Tebon, I. Lampronti, S. Huang, L. Wiszniewski, M.T. Scupoli, A. Bragonzi, R. Gambari, G. Berton and G. 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Díaz Martín",authors:[{id:"81752",title:"Dr.",name:"Rosa Patricia",middleName:null,surname:"Arias Llorente",fullName:"Rosa Patricia Arias Llorente",slug:"rosa-patricia-arias-llorente"},{id:"88980",title:"Prof.",name:"Carlos",middleName:"GarcÃa",surname:"Bousoño",fullName:"Carlos Bousoño",slug:"carlos-bousono"}]},{id:"34295",title:"Improving the Likelihood of Success in Trials and the Efficiency of Delivery of Mucolytics and Antibiotics",slug:"improving-the-likelihood-of-success-in-trials-and-efficiency-of-delivery-of-mucolytics-and-antibioti",signatures:"Carlos F. Lange",authors:[{id:"87618",title:"Prof.",name:"Carlos",middleName:"Frederico",surname:"Lange",fullName:"Carlos Lange",slug:"carlos-lange"}]},{id:"34296",title:"Airways Clearance Techniques in Cystic Fibrosis: Physiology, Devices and the Future",slug:"airway-clearance-techniques-in-cystic-fibrosis-physiology-devices-and-the-future",signatures:"Adrian H. Kendrick",authors:[{id:"81571",title:"Dr.",name:"Adrian",middleName:"H.",surname:"Kendrick",fullName:"Adrian Kendrick",slug:"adrian-kendrick"}]},{id:"34297",title:"The Physiotherapist's Use of Exercise in the Management of Young People with Cystic Fibrosis",slug:"the-physiotherapist-s-use-of-exercise-in-the-management-of-young-people-with-cystic-fibrosis",signatures:"Allison Mandrusiak and Pauline Watter",authors:[{id:"84089",title:"Dr.",name:"Allison",middleName:null,surname:"Mandrusiak",fullName:"Allison Mandrusiak",slug:"allison-mandrusiak"},{id:"87978",title:"Dr.",name:"Pauline",middleName:null,surname:"Watter",fullName:"Pauline Watter",slug:"pauline-watter"}]},{id:"34298",title:"Exercise Performance and Breathing Patterns in Cystic Fibrosis",slug:"exercise-performance-and-breathing-patterns-in-cystic-fibrosis",signatures:"Georgia Perpati",authors:[{id:"79721",title:"Dr.",name:"Georgia",middleName:null,surname:"Perpati",fullName:"Georgia Perpati",slug:"georgia-perpati"}]}]}]},onlineFirst:{chapter:{type:"chapter",id:"75059",title:"Antimicrobial Potential of Pomegranate Extracts",doi:"10.5772/intechopen.95796",slug:"antimicrobial-potential-of-pomegranate-extracts",body:'
1. Introduction
Infectious diseases caused by pathogenic microbes are a fundamental problem and remain one of the major factors behind high morbidity and mortality across the world, especially in developing countries. This is exacerbated by the world-wide emergence of antibiotic-resistant pathogens which has in turn given increased urgency to the discovery of new antimicrobial compounds, including those derived from plants [1, 2].
The pomegranate, fruit of the Punica granatum L. tree, is one of oldest recorded edible fruits and it has been used as a folklore medicine since ancient times. There are records of it being used to treat inflammatory diseases and disorders of the digestive tract in the Ayurvedic and Unani systems [3, 4]. In terms of infections, the ancient Egyptians used it in the treatment of tapeworms and other parasites [5], whereas other cultures have used pomegranates to treat diarrhea and dysentery [6, 7, 8], although at the time they would not have known that pathogenic microbes were responsible. In more recent times, the pomegranate has been extensively and scientifically studied for its antimicrobial potential in a diversity of areas such skin infections, dentistry, food preservation etc. [9].
The phytochemistry of pomegranate extracts is well described in the literature [10, 11, 12] and they are known to be rich in bioactive compounds especially polyphenolics including anthocyanins and ellagitannins, in particular punicalagin, which is in the highest proportion [13]. As will be seen, it has become apparent that the pomegranate possesses unusual broad-spectrum potency against a wide range of species, which generally correlates with its polyphenol concentration.
In this chapter we aim to summarise published research into pomegranate extracts as antimicrobials and discuss some of the purported mechanisms behind such activity. Finally, the enhancement of antimicrobial activity by co-administration with metal ions is considered.
2. Activity against bacteria
Staphyllococcus aureus (S. aureus) and methicillin resistant Staphyllococcus aureus (MRSA) have received the greatest attention as targets for pomegranate extract activity. In 2010, the antibacterial activity of crude and purified extracts of pomegranate peel were assessed by Panichayupakaranant et al. 8 mg crude peel loaded discs showed 20 mm and 30 mm zone of inhibition against clinical isolates of S. aureus and E. coli, respectively. The purified peel extract discs, loaded up to 8 mg, exerted a range of zones of inhibition between 15-20 mm for S. aureus and 20-30 mm for E. coli. Using standardized peel extract, minimum inhibitory concentrations (MIC) values of 0.016, 0.008, and 0.008–0.016 mg/mL were obtained for S. aureus, S. epidermidis and Propionibacterium acnes respectively. Tetracycline was used as a positive control in this study and standardized pomegranate rind extract showed lower activity in zone of inhibition assays, with tetracycline also showing a lower minimum inhibitory concentration (MIC) [14]. A methanolic extract of pomegranate peel inhibited biofilm formation and eradicated pre-formed biofilm of S. aureus, MRSA, E. coli in the concentration range 25 to 150 μg/mL [15]. In the same study, ellagic acid showed biofilm inhibition and eradication activity at somewhat lower concentrations (5–40 μg/mL) than pomegranate peel extract. Furthermore, while pomegranate extract was able to inhibit the growth of S. aureus, it also suppressed enterotoxin production [5].
Pomegranate extracts have shown antimicrobial activity against to a range of oral microbes. It has been found that pomegranate extract powder at 1 mg/mL was effective against primary and secondary colonizer bacteria of dental plaque: F. nucleatum, P. gingivalis, P. intermedia, S. mutans and A. actinomycetomomitans [16]. In another in vitro study, pomegranate alcoholic extracts have been tested on bacteria which are collected from patients who have tooth decay or periodontitis and inhibited a range of bacteria in both planktonic and biofilm conditions [17]. Synergistic bactericidal activity against S. mutans and R. dentocariosa was reported for pomegranate extract in combination with other plant polyphenolic extracts, honey and myrtle [18].
Moreover, ‘standardized’ pomegranate peel extract showed higher antimicrobial activity than other parts of pomegranate (flower, leaf, stem) and ciprofloxacin (2 mg/mL) against S. mutans, Salmonella mitis and L. acidophilusin in a zone of inhibition assay [19]. Again, pomegranate gel showed an inhibitory activity against S. mutans, Salmonella sanguis, and S. mitis [20]. This gel also showed antiadhesive activity against S. mutans and S. mitis at lower than minimum inhibitory concentrations to a glass surface. In addition to inhibition activity on bacterial growth and biofilm, pomegranate extracts showed antiadhesive activity for S. mutans adherence on tooth surface in orthodontic treated patients [21]. In other clinical studies, the antiplaque effect and prophylactic benefits of pomegranate have been highlighted [22]. Recently, a systematic review and meta-analysis has been carried out by Martins et al. [23], where natural antimicrobial phenolic compounds were compared with synthetic antimicrobials by using 16 clinical studies for qualitative analysis, and 12 studies for meta-analysis. For the meta-analysis, six clinical trials were evaluated for the comparison of natural antimicrobial phenolic compounds, including pomegranate extract mouthwash, and synthetic antimicrobials. It was found that natural antimicrobial phenolic compounds are less effective than chlorhexidine for biofilm control, although it showed similar reduction of the oral microbes count which was sub-grouped as total microorganisms, Streptococcus mutans, and Streptococcus spp. according to type of microorganisms.
Due to its antimicrobial and antioxidant properties, pomegranate extract has been studied for its preservation potential use in the food industry. Kannat et al. [24] did a study to evaluate the antimicrobial activity of pomegranate peel against common food spoilers and potential pathogens. It was shown that pomegranate peel extract increased the shelf-life of chicken and meat products and showed antimicrobial activity against to S. aureus, B. cereus with a minimum inhibitory concentration at 0.01%. However, it did not show antimicrobial activity for E. coli and S. typhimurium even at higher concentrations. Other researchers showed that pomegranate extracts were less effective against Gram-negative compared to Gram-positive bacteria, probably due to the differences in cell wall structure [25, 26]. Moreover, pomegranate has been studied in a novel and smart multi-functional hydrogel (MFH) system as a food packaging material since it is easy to monitor of the color change due to changes in conditions such as pH and temperature. The MFH with pomegranate extract showed promising antimicrobial activity on pasteurized milk and cheese over a 7-day period [27]. Pomegranate peel extract was also added in a film formulation to produce a material for food packaging materials with antimicrobial and antioxidant effects. This film formulation was found to restrict the growth of L. monocytogenes in pork samples inoculated with this bacterium [28].
The activity of pomegranate extract against bacteria is summarized in Table 1.
Antibacterial activity of pomegranate extracts against different bacteria.
3. Activity against fungi
Treatment of fungal infections is a big challenge because of the eukaryotic nature of fungal cells that have similarity with host cells. While there are some drugs in the treatment of fungal infections available in the clinic, they are limited and there is a need for new alternatives [29, 30]. There are reports showing antifungal activity of pomegranate extracts, especially against Candida species [5, 7, 31], which are part of the normal microbiota of human gastrointestinal, oral, and vaginal mucosae. However, they can cause superficial infections and especially in immunosuppressed patients, they can cause severe infectious problems. In one study, punicalagin showed superior antifungal activity than the conventional fluconazole in an in vitro time-kill assay. In addition, punicalagin caused a significant change in Candida morphology, and alteration in budding pattern and pseudo hyphae when yeasts were treated with a sub-inhibitory concentration of punicalagin [32]. In another study, pomegranate extract showed superior inhibitory action against C. tropicalis while fluconazole and voriconazole, which are commonly prescribed azoles for fungal infections, have been ineffective against C. tropicalis [33].
The potential of pomegranate extract has been studied against fungi in in vitro biofilm assays. Microbes in biofilms have substantially different characteristics to those of their free-living planktonic counterparts [34, 35]. In particular, microbes in biofilms are concealed and therefore protected from antifungal agents and plant extracts [36, 37]. Pomegranate extract and its one of the major components ellagic acid were shown to exert a reduction in biofilm formation and eradicated pre-formed biofilm of C. albicans in an in vitro biofilm study [15]. Spray-dried microparticles containing pomegranate extract showed antifungal activity in in vitro assays under both planktonic and biofilm conditions [38]. In addition, the inhibitory effect of pomegranate extract on the growth of Candida albicans was demonstrated in an in vivo study [31]. In another study, similar effects have been obtained against to Candida mycoderma using different parts of pomegranate, fresh fruit and sterile juice [39].
In addition to Candida species, pomegranate extracts showed inhibitory activity against dermatophytes, which are fungi which use keratin as a source of nutrition and may cause infection in keratinized tissue parts such as nails, skin and hair follicles. Pomegranate peel extract and punicalagin exerted potent antifungal activity against to T. rubrum (125 μg/mL), T. mentagrophytes (125 μg/mL), M. canis (250 μg/mL) and M. gypseum (250 μg/mL). Punicalagin at a concentration of 62.5 μg/mL also inhibited T. rubrum spore germination, and it was further found that punicalagin 62.5 μg/mL and nystatin 0.78 μg/mL showed similar inhibition in hyphal growth of T. rubrum [40]. Moreover, pomegranate extracts have been researched for use as natural preservatives due to their antifungal (in addition to antibacterial) activities [41]. Pomegranate peel extract showed inhibition activity against to Aspergillus niger and Aspergillus parasiticus in a zone of inhibition assays [42]. Pomegranate extract showed inhibitory effects against fungal pathogens which are responsible for fruit and vegetable decay. Punicalagin was proposed as the main compound in the extracts providing the observed antifungal activity and it has been found effective in mycelial growth inhibition against phytopathogenic filamentous fungi such as Fusarium vertillicoides, Mucor indicus, Penicillium citrinum, Rhizopus oryzae and Trichoderma recei [43]. Also, the growth rate of pathogens presented a negative correlation with total punicalagin content, and it has thus been suggested that pure punicalagin may be used as a control agent in storage disease to prevent the excessive use of synthetic fungicides [44, 45].
The activity of pomegranate extract against fungal microbes is summarized in Table 2.
Antifungal activity of pomegranate extracts against different fungi.
4. Activity against viruses
Pomegranate extracts have been examined as an alternative treatment for viral infections [46, 47, 48]. A number of studies have shown that polyphenolic compounds have broad-spectrum antiviral activity, by inhibiting viral DNA and RNA, and directly binding the viral particles. It has also been suggested that polyphenols could provide antiviral activity during intracellular replication [49, 50, 51, 52].
Pomegranate peel extract showed antiviral activity against the influenza virus. In a study by Sundararajan et al. [53], complete inactivation of influenza virus was observed with 1600 μg/mL pomegranate polyphenols, and 400 μg/mL of same extract showed 99% or more titer reduction in only 5 minutes treatment. This result was similar to another study which showed complete inactivation of H3N2 influenza virus within 30 minutes of treatment and a significant viral reduction with approximately 1 μg/mL pomegranate polyphenols. An in vitro study, showed that pomegranate polyphenol extract inhibited viral replication in addition to its virucidal effect – they also obtained same activity for punicalagin and suggested punicalagin is the main compound in pomegranate extract for antiviral activity [54]. In an in vivo mouse model study, pomegranate polyphenols applied to the lung were found to reduce influenza infection, without toxic effect to the host [55, 56].
Hepatitis C virus (HCV) is the main factor in end-stage liver disease and approximately 170 million people are chronically infected with HCV. Pomegranate ellagitannins, punicalagin, punicalin and ellagic acid, blocked and inhibited the NS3/4A protease which is a viral polyprotein responsible for processing and replication in HCV. Moreover, punicalagin and punicalin significantly decreased the HCV replication in an in vitro cell culture system [57]. The more prevalent adenovirus (ADV) in Hep-2 host cells has also shown susceptibility to pomegranate crude extract, fractions, and main phenolic compounds. It has been found that a n-butanol fraction of pomegranate peel extract and gallic acid showed the highest antiviral activity against ADV. Furthermore, the crude extract, n-butanol fraction and gallic acid inhibited ADV replication in the post-adsorption phase [58].
Herpes simplex virus (HSV) is from the Herpes viridae family and infects a high proportion of the populous. HSV-1 is generally responsible for cold sores and encephalitis, whereas HSV-2 is the main causative agent of anogenital infections, which can also infect neonates via the mother [59, 60]. Pomegranate rind extract (PRE) and its major ellagitannin compound, punicalagin, showed virucidal activity against HSV-1. While punicalagin has greater virucidal activity than an equivalent mass of pomegranate rind extract, PRE showed better antiviral activity than punicalagin. Moreover, PRE demonstrated comparable activity to acyclovir against HSV-1 and HSV-2, in addition to antiviral activity against acyclovir-resistant HSV-1 [48]. PRE is thus a promising new alternative treatment for HSV-1 since currently acyclovir is the gold standard treatment in HSV infections [61].
Studies have suggested that the antiviral activity of pomegranate extract originates from its hydrolysable tannins and polyphenols, especially punicalagin and gallagic acid. However, in one study, four flavonoids, ellagic acid, caffeic acid, luteolin and punicalagin, from pomegranate peel extract were studied against influenza virus and only punicalagin showed an inhibitory effect. The antiviral activity of pomegranate rind extract has been patented in Japan based on pomegranate peel extract ability to prevent the growth and kill viruses on the surfaces [46, 47]. The activity of pomegranate extract against viruses is summarized in Table 3.
Antiviral activity of pomegranate extracts against different viruses.
5. Activity against parasites
Parasitic infections remain a significant global problem, affecting the health of hundreds of millions of people annually, especially in countries with low economic and social conditions. In addition, the increased world-wide resistance to conventional drugs is making most of currently used drugs less effective. As a result of this situation, the development of new drugs from medicinal plants for parasites is as important as for other microbes [62]. Different parts of Punica granatum L., root, stem bark, and rind of fruit, have been used commonly as vermifugal and taenicide agents [63]. The antiprotozoal activity of the pomegranate has been determined and in folkloric medicine, it has been used as anthelminthic especially against tapeworms and for diarrhea [64, 65]. A methanolic extract of pomegranate leaves showed nematicide activity and hepatoprotective activity against carbon tetrachloride induced hepatoxicity [66]. Extracts of pomegranate showed anti-schistosomal activity against Shistosoma mansoni in both in vitro and in vivo conditions [67]. In addition, it caused reduction or complete loss of motor activity, lethality and ultra-morphological changes in adult worms [68]. There is thus potential for the treatment of schistosomiasis.
Al-Musayeib et al. reported the antiparasitic activity of pomegranate rind extract against Plasmodium falciparum [69]. Pomegranate juice was found to exert dose-dependent activity against Leishmania major promastigotes and, at >80 μL/mL, gave significantly greater reduction than the positive control, Pentostam. Furthermore, mice that were orally treated with pomegranate juice, showed significantly reduced cutaneous leishmaniasis lesions compared to untreated mice [70]. Calzada et al. demonstrated pomegranate antiprotozoal activity against Entameoba histolytica and Giardia lamblia that cause diarrheic dysentery [71]. Pomegranate peel suspension also affected C. parvum in different stages and finally caused parasite death in an in vivo murine model; furthermore, pomegranate suspension did not cause any negative change in the mice ileal tissue [72]. In another study, pomegranate extract showed activity against T. vaginalis, both in vitro and clinically. Patients with T. vaginalis infection were treated with pomegranate juice and symptoms were found to have cleared after two months [73]. The activity of pomegranate extract against parasites is summarized in Table 4.
Antiparasitic activity of pomegranate extracts against different parasites.
6. Potential mechanisms of antimicrobial activity of pomegranate extracts
From the preceding sections it is clear that there is compelling evidence demonstrating the broad-spectrum antimicrobial activity of pomegranate extracts [74, 75, 76]. However, the precise mechanism behind this activity is not fully understood. The mode of antimicrobial action of polyphenols, in general, is also unknown, although some suggested mechanisms include membrane disruption, toxicity against microorganisms, the ability of complex formation with metal ions and enzyme inactivation [77, 78, 79]. The antimicrobial activity of pomegranate has been associated with polyphenolic tannins, especially punicalagin and ellagic acid content in the extract [80, 81, 82]. However, pomegranate extracts are a complex mixture containing a variety of secondary compounds and interplay between these components may be a factor in antimicrobial activity, with multiple mechanisms operating independently [83].
An antimicrobial mechanism suggested for polyphenolic compounds is based on the precipitation ability of these compounds with bacterial cell membrane proteins which leads to bacterial cell lysis [84]. In addition, polyphenols could inhibit microbial enzymes by reacting with sulfhydryl groups or nonspecific interactions with proteins [85]. In that vein, phenolic compounds can bind the protein sulfhydryl groups and make them unavailable for microbial growth [86]. In addition, it has been reported that polyphenols can damage the microbe respiratory chain by decreasing the oxygen consumption and thus limiting the oxidation of NADH [87].
It has been hypothesized that the antibacterial activity of phenolic acids and flavonoids could cause a decrease in membrane fluidity by giving damage to the bacterial cytoplasmic membrane [88]. Phenolic acids can cause hyper acidification when they interphase with the plasma membrane. This situation would cause an alteration in cell membrane by making it more permeable. This mechanism could explain why phenolic acids show different antimicrobial activity levels against different pathogenic microorganisms [89, 90]. One of the possible mechanisms could be related to hydroxyl groups of polyphenols. The position of OH group in the aromatic ring and the length of saturated side chain could be a cause of antimicrobial activity of polyphenols [91]. Hydroxyl groups can bind to bacteria cell membranes and interfere with processes, such as ion pumping. In addition, OH groups can interact with active site of enzymes and disturb the metabolism of microorganisms [91].
Pomegranate extract exerted an inhibition activity against biofilms, in addition to their planktonic counterparts. Since microbes act differently under biofilm conditions compared to their planktonic form, there are some suggested pathways about polyphenols biofilm eradication and formation inhibition activities, although still unconfirmed. The mechanism behind growth and biofilm inhibition by pomegranate extracts cause protein precipitation and enzyme inactivation [81, 92]. Pomegranate extract could precipitate proteins which play major role in biofilm formation, like adhesins. Moreover, major hydrolysable tannins in pomegranate extract such as ellagic acid can change the surface charge and reduce the cell-substratum interactions and biofilm formation and development on different surfaces [93]. It is well known that tannins have astringency properties, and this feature can play a part in biofilm disruption [94, 95]. Different studies have shown the activity of pomegranate on bacterial attachment and therefore biofilm formation. It has been demonstrated that Punica granatum L. showed a specific antimicrobial action on dental plaque, which is a complex biofilm on tooth, by inhibiting adherence mechanism of oral microbes to dental surface via disturbing polyglucan synthesis [17, 96, 97]. Moreover, Vasconcelos et al. [98] used Punica granatum L. in a gel formulation using increasing and doubled concentrations of the diluted solutions of the gel with ranging concentrations from 1:1 to 1:1024, and similar results obtained. The gel formulation inhibited the adherence of different bacterial strains and a yeast, C. albicans, in the oral cavity and affected preformed biofilm.
There are some reports suggesting that the inhibition of quorum sensing (QS) could play role in the biofilm inhibition activity of pomegranate [99, 100]. QS is a communication system between bacteria in a biofilm, and provides a network involving nutrients, defense against other microorganisms, virulence and biofilm formation. More importantly, QS helps microbes to escape from host immune response [101, 102]. Therefore, inhibition of QS is quite important in order to overcome microbial infectious diseases and resistant pathogenic microbes. For the evaluation of QS inhibitors, Chromobacterium violaceum has been used as a biosensor since it produces violacein, purple pigment color, in response to QS regulation [103]. Pomegranate inhibited the QS of two bacterial strains which are Chromobacterium violaceum (by affecting purple pigment production) and P. aeruginosa (by decreasing bacterial swarming motility) [104, 105]. In another study, different compounds from herbs, fruits and plant extracts have been studied for their QS activity, with resveratrol and pomegranate extract demonstrating the highest inhibition activities. The QS activity of pomegranate has been associated with ellagic acid content of pomegranate extract (85% punicalagin, 7% free ellagic acid) since ellagic acid showed 86% inhibition at a low concentration of 4 μg/mL. However, the anti-QS activity of punicalagin is also believed important in pomegranate extracts [106]. Tannin-rich fraction of pomegranate rind extract showed inhibition of biofilm formation and motility of E. coli and repressed the expressions of curli genes (csgB and csgD) and various motility genes (fimA, fimH, flhD, motB, qseB, and qseC) [107]. Similarly, punicalagin significantly decreased the expression of QS-related genes (sdiA and srgE) of Salmonella [108].
The chemical structure of tannins has importance in bacterial growth inhibition. For example, hydrolysable tannins were found to give lower minimum inhibitory concentration than condensed tannins [109]. The degree of galloylation has an effect on antibacterial activity since a higher degree of galloylation have more protein binding capacity and higher affinity for iron. However, the antibacterial activity is not only correlated to galloyl groups and galloylation, also it is correlated to configuration of the digalloyl or trigalloyl groups that attached to glucose core [110, 111, 112]. In addition, free galloyl groups have a major role in antimicrobial activity of ellagitannins which are abundant secondary compounds in pomegranate extracts [12, 113]. Punicalagin showed the broad-spectrum antimicrobial activity and it has a gallagyl moiety [114]. However another ellgitannin, granatin A, which does not have free galloyl groups, did not show antibacterial activity [115]. In a study done by Reddy et al., ellagic acid, gallagic acid, punicalin and punicalagin were purified and tested for their antiplasmodial and antimicrobial activities. Gallagic acid and punicalagin showed the strongest effects on the growth of bacteria and fungi and it has been suggested that the ellagic acid moiety is not important compared to the gallagyl and hexahydroxydiphenol (HHDP) moieties for the inhibition of microbes [116]. The degradation of punicalagin to ellagic acid, via punicalin and hexahydroxydiphenic acid is shown in Figure 1.
Figure 1.
Reduction of punicalagin, punicalin and HHDP to ellagic acid, adopted from Seeram et al. [3, 12].
The antimicrobial activity of plants has been studied extensively and many active secondary compounds have been identified. However, it should not be ignored that plant extracts with antimicrobial activities contain potentially many secondary compounds. Therefore, it is not easy to attribute the biological activity of plant extracts to only a single compound or a group of secondary compounds. There is a high possibility that plant extracts show antimicrobial activity due to synergistic effect of different compounds [117].
7. Enhanced antimicrobial activity of pomegranate extracts with metal ions
There are many reports showing the antimicrobial activity of heavy metals such as iron, copper, silver, manganese and zinc, while many bacteria have mechanism for the detoxification of heavy metals [118, 119]. However, although metal ions have a strong antimicrobial effect, they can also be cytotoxic to human cells, therefore, the use of these metals may have limitations in healthcare [120, 121].
Stewart et al. [122] investigated the potentiated antimicrobial activity of pomegranate rind extract (PRE) in combination with metal ions. In their study, the aim was to exert short term exposure of pomegranate rind extract and ferrous sulfate combination on bacteriophage levels for 3 minutes. This combination showed highly significant synergistic activity and reduced the bacteriophage levels in a short-term exposure. This short screening time was necessary for this experiment due to low stability of pomegranate rind extract/ferrous salt solution which, via a Fenton reaction caused Fe2+ to oxidize to Fe3+ with concomitant solution blackening. To overcome this instability problem, potentiated/synergised antimicrobial activity of pomegranate rind extract has since been examined using alternative metal ions [48, 123, 124].
McCarell et al. [123] investigated the antimicrobial activity of PRE with 4.6 mM FeSO4, CuSO4, MnSO4, ZnO and also studied antimicrobial activity of PRE/metal salt combinations plus vitamin C which was added as a stabilizer. They observed significant synergistic antibacterial activity against E. coli, Ps. Aeruginosa, S. aureus and P. mirabilis when they combined PRE with Cu (II) ions. Moreover, with the addition of vitamin C as antioxidant, the antimicrobial activity increased significantly for PRE/Fe (II) and PRE/Cu (II) combinations against S. aureus. In another study, researchers used the vanillin complexes with different metal ions using the agar diffusion method and it was found that the vanillin and metal salts showed an enhanced activity against S. aureus, E. coli, K. pneumanie, P. aeruginosa and C. albicans. The results from both studies indicated that the addition of metal ions, especially copper salts, can significantly enhance antibacterial activity of a natural product [123, 125].
Significantly enhanced virucidal activity of PRE was later observed against HSV-1, HSV-2 and acyclovir-resistant HSV-1 by Houston et al. [48] in combination with different Zn (II) ion salts, including zinc sulphate, zinc citrate, zinc stearate and zinc gluconate, with a maximum of 6 log reduction observed. Unlike PRE and Fe2+, this activity was not time-limited, and was not associated with blackening. Importantly, this activity was also retained when applied to epithelial surfaces prone to Herpes infection, including buccal and vaginal mucosae [126], indicating potential treatment for cold sores and anogenital Herpes.
The mechanism for the synergistic antimicrobial activity of pomegranate extract in combination with metal ions is not clear, although there are some putative suggested mechanisms for this enhanced antimicrobial activity. For instance, it has been suggested that pomegranate tannins can form a ‘complex’ with metallic ions and this complex could show enhanced toxicity to microbes [127]. Furthermore, PRE could show enhanced activity due to redox cycling of the associated metal ion which increases local levels of reactive oxygen species (ROS). For example some antibiotics e.g. bleomycin showed enhanced ROS production via the ability to bind to ferrous ions which resulted in enhanced toxicity against microbes [128].
The enhancement of antimicrobial activity of pomegranate rind extract with metal ions is important in terms of improved efficacy against antibiotic resistant pathogens, since this enhancement could reduce resistance of microbes by inhibiting their microbial adaptability features [8, 32].
8. Conclusions
The pomegranate has a long history of use as a folklore medicine for its ability to address microbial infections. Published research, as outlined in this chapter, clearly supports this and has shown that pomegranate extracts possess an unusual and potent broad-spectrum of activities against bacteria, fungi, viruses and parasites.
There is some variation in the literature in terms of the levels of antimicrobial activity of pomegranate extracts, which could be attributed to different harvesting time and type of pomegranate cultivars, and use of varying microbial strains. However, it is also apparent that different workers have used a range of approaches to obtain ‘pomegranate extract’, with extraction methods sometimes being poorly described. As such, a lack of standardized test extracts presents a challenge in attempting to make quantitative comparisons. As a complex mixture, pomegranates extracts have the innate ability to inhibit resistance, even more so when used alongside a synergizing metal ion.
Acknowledgments
We would like to thank to Turkish Ministry of Education for supporting Vildan Celiksoy’s PhD project.
Conflict of interest
The authors declare no conflict of interest.
\n',keywords:"antimicrobial, bacteria, fungi, viruses, parasites, polyphenols, pomegranate extracts, biofilm, tannins, punicalagin",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/75059.pdf",chapterXML:"https://mts.intechopen.com/source/xml/75059.xml",downloadPdfUrl:"/chapter/pdf-download/75059",previewPdfUrl:"/chapter/pdf-preview/75059",totalDownloads:43,totalViews:0,totalCrossrefCites:0,dateSubmitted:"September 21st 2020",dateReviewed:"January 4th 2021",datePrePublished:"February 11th 2021",datePublished:null,dateFinished:"February 3rd 2021",readingETA:"0",abstract:"The search for plant extracts with efficacious antimicrobial activity remains important, partly due to fears of the side effects associated with conventional antibiotics and to counter the emergence of resistant microorganisms. Pomegranate extracts have been used for millennia for their anti-infective properties, with activity more recently being attributed to its rich composition of ellagitannins and other secondary polyphenolic compounds. This chapter highlights the growing number of publications that have probed the activity of pomegranate extracts against microbes. Research generally supports folklore claims and has shown that pomegranate extracts possess unusual and potent broad-spectrum activities against Gram-positive and Gram-negative bacteria (planktonic and biofilm), fungi, viruses and parasites. Possible pathways/mechanisms of antimicrobial activity of pomegranate extracts are discussed and enhancement/potentiation of such activity using metal ions considered.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/75059",risUrl:"/chapter/ris/75059",signatures:"Vildan Celiksoy and Charles M. Heard",book:{id:"10171",title:"Pomegranate",subtitle:null,fullTitle:"Pomegranate",slug:null,publishedDate:null,bookSignature:"Dr. Vasiliki Lagouri",coverURL:"https://cdn.intechopen.com/books/images_new/10171.jpg",licenceType:"CC BY 3.0",editedByType:null,editors:[{id:"232589",title:"Dr.",name:"Vasiliki",middleName:null,surname:"Lagouri",slug:"vasiliki-lagouri",fullName:"Vasiliki Lagouri"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Activity against bacteria",level:"1"},{id:"sec_3",title:"3. Activity against fungi",level:"1"},{id:"sec_4",title:"4. Activity against viruses",level:"1"},{id:"sec_5",title:"5. Activity against parasites",level:"1"},{id:"sec_6",title:"6. Potential mechanisms of antimicrobial activity of pomegranate extracts",level:"1"},{id:"sec_7",title:"7. Enhanced antimicrobial activity of pomegranate extracts with metal ions",level:"1"},{id:"sec_8",title:"8. Conclusions",level:"1"},{id:"sec_9",title:"Acknowledgments",level:"1"},{id:"sec_12",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Bereket W, Hemalatha K, Getenet B, Wondwossen T, Solomon A, Zeynudin A, Kannan S. Update on bacterial nosocomial infections. Eur Rev Med Pharmacol Sci. 2012 Aug 1;16(8):1039-1044.'},{id:"B2",body:'Savard P, Perl TM. A call for action: managing the emergence of multidrug-resistant Enterobacteriaceae in the acute care settings. Current opinion in infectious diseases. 2012 Aug 1;25(4):371-7.'},{id:"B3",body:'Seeram NP, Adams LS, Henning SM, Niu Y, Zhang Y, Nair MG, Heber D. In vitro antiproliferative, apoptotic and antioxidant activities of punicalagin, ellagic acid and a total pomegranate tannin extract are enhanced in combination with other polyphenols as found in pomegranate juice. 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N-acylhomoserine lactone regulates violacein production in Chromobacterium violaceum type strain ATCC 12472. FEMS microbiology letters. 2008 Feb 1;279(1):124-30.'},{id:"B104",body:'Koh KH, Tham FY. Screening of traditional Chinese medicinal plants for quorum-sensing inhibitors activity. Journal of Microbiology, Immunology and Infection. 2011 Apr 1;44(2):144-8.'},{id:"B105",body:'Zahin M, Hasan S, Aqil F, Khan M, Ahmad S, Husain FM, Ahmad I. Screening of certain medicinal plants from India for their anti-quorum sensing activity.'},{id:"B106",body:'Truchado P, Tomás-Barberán FA, Larrosa M, Allende A. Food phytochemicals act as quorum sensing inhibitors reducing production and/or degrading autoinducers of Yersinia enterocolitica and Erwinia carotovora. Food Control. 2012 Mar 1;24(1-2):78-85.'},{id:"B107",body:'Yang Q, Wang L, Gao J, Liu X, Feng Y, Wu Q, Baloch AB, Cui L, Xia X. 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Fast LC–MS analysis of gallotannins from mango (Mangifera indica L.) kernels and effects of methanolysis on their antibacterial activity and iron binding capacity. Food research international. 2012 Jan 1;45(1):422-6.'},{id:"B112",body:'Tian F, Li B, Ji B, Zhang G, Luo Y. Identification and structure–activity relationship of gallotannins separated from Galla chinensis. LWT-Food Science and Technology. 2009 Sep 1;42(7):1289-95.'},{id:"B113",body:'Farha AK, Yang QQ, Kim G, Li HB, Zhu F, Liu HY, Gan RY, Corke H. Tannins as an alternative to antibiotics. Food Bioscience. 2020 Sep 3:100751.'},{id:"B114",body:'Machado TD, Leal IC, Amaral AC, Santos K, Silva MG, Kuster RM. Antimicrobial ellagitannin of Punica granatum fruits. Journal of the Brazilian Chemical Society. 2002 Sep;13(5):606-10.'},{id:"B115",body:'Shimozu Y, Kimura Y, Esumi A, Aoyama H, Kuroda T, Sakagami H, Hatano T. Ellagitannins of Davidia involucrata. 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AFFILIATION
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Authors are responsible for ensuring all addresses and emails provided are correct. Under affiliation(s) all Authors should indicate where the research was conducted. Please note that no changes to the affiliation(s) can be made after the chapter has been published.
Substantially contribute to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work
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Participate in drafting or revising the work
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Approve the final version of the work to be published.
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All contributors who meet these criteria are listed as Authors. Their exact contributions should be described in the manuscript at the time of submission.
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Conversely, all contributors who do not meet these criteria should be listed in the Acknowledgments section of the manuscript, along with a short description of their specific contributions.
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CHANGES IN AUTHORSHIP
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If it is felt necessary to make changes to the list of Authors after a manuscript has been submitted or published, it is the responsibility of the Author concerned to provide a valid reason to amend the published list. Additionally, all listed Authors must verify and approve the proposed changes in order for any amendments to be made.
\n\n
AFFILIATION
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Authors are responsible for ensuring all addresses and emails provided are correct. Under affiliation(s) all Authors should indicate where the research was conducted. Please note that no changes to the affiliation(s) can be made after the chapter has been published.
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Policy last updated: 2017-05-29
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