Classification of congenital heart defects which become symptomatic in the neonatal period.
\r\n\t
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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"314",title:"Regenerative Medicine and Tissue Engineering",subtitle:"Cells and Biomaterials",isOpenForSubmission:!1,hash:"bb67e80e480c86bb8315458012d65686",slug:"regenerative-medicine-and-tissue-engineering-cells-and-biomaterials",bookSignature:"Daniel Eberli",coverURL:"https://cdn.intechopen.com/books/images_new/314.jpg",editedByType:"Edited by",editors:[{id:"6495",title:"Dr.",name:"Daniel",surname:"Eberli",slug:"daniel-eberli",fullName:"Daniel Eberli"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"53683",title:"Pre and Postoperative Management of Pediatric Patients with Congenital Heart Diseases",doi:"10.5772/66990",slug:"pre-and-postoperative-management-of-pediatric-patients-with-congenital-heart-diseases",body:'\nIn the following paragraphs of this chapter, the general features of various congenital heart defects, their clinical symptoms and treatment principles for the management of congenital heart defects that become symptomatic in neonates will be discussed. In this context, the special measures for the initial treatment of the most common defects are presented [1–8, 11].
\nBased on many epidemiological studies, the actual incidence of congenital heart defects is 8–11 per 1000 live births independent of ethical background, social welfare or medical standards. As a rule thumb nearly half of these children require any form of surgical or interventional intervention within the first year of life. With adequate management, more than 90% of these children can reach adulthood and lead a relatively normal life.
It is typical for the different congenital heart defects to present and become manifest at different times in early life. Of most importance are the very early phase when the patent ductus arteriosus closes for all ductal-dependent cardiac defects; the next important timeframe of clinical manifestation is the reduction in pulmonary vascular resistance (PVR) for defects with left-to-right shunt.
Typical leading symptoms for the presentation of congenital heart defects in neonates are as follows:
\nHeart failure or cardiogenic shock (usually in the first or second week of life if there is left heart obstruction; for shunt defects typically not until after the drop in pulmonary resistance at the age of 2–8 weeks)
Cyanosis
Additional important clinical symptoms that may lead to the diagnosis of a congenital heart defect in neonates are the presence of a murmur on auscultation or any form of arrhythmia (rarely as the primary symptom of a congenital heart defect).
\nThe characteristic clinical signs of heart failure in neonates are as follows:
\nTachypnea, dyspnea, thoracic retractions
Rarely but possible pulmonary edema mainly due to overflow
Tachycardia
Hepatomegaly
Failure to thrive, difficulty in feeding, increased sweating, abnormal sleepiness
Pallor, prolonged capillary refill time
It is evident that the clinical symptoms of neonatal heart failure are unspecific and may be similar to the clinical symptoms of sepsis. Therefore, many neonates with heart failure are treated for suspected sepsis.
\nIn particular, cardiac defects with left-sided obstruction (coarctation of the aorta, critical aortic stenosis, hypoplastic left heart syndrome), or typically become manifest as early as the first 1–2 weeks of life with the clinical symptoms of cardiogenic shock caused by early duct closure.
Cyanosis is a clinical sign that becomes evident when about 5% of the hemoglobin is deoxygenated. In neonates with polycythemia (Hb >20 g/dl), this may be present even without hypoxemia, in patients with anemia this may be overseen. To avoid this, pulse oximetry at all four limbs is the standard of care.
Cardiac cyanosis can be the result of either reduced lung perfusion due to a right-to-left shunt, complete venous mixing in patients with total anomalous pulmonary venous return or intracardiac mixing of systemic and pulmonary venous blood. Methemoglobinemia is another rare cause for cyanosis. In addition, cyanosis can be caused by abnormality in the central nervous system (e.g., after cerebral hemorrhage or in cases with central apnea in premature neonates, etc.)
All newborns should have a neonatal screening for congenital heart defects immediately after birth and 12 h later. Today ECHO is the main diagnostic tool for secondary investigation and to rule out or confirm congenital heart defects.
\nIf the diagnosis can not be immediately confirmed by echocardiography, an attempt of treating the neonate with intravenous prostaglandin E1 is justified.
\nThe hyperoxia test is no longer standard of care. If there is no adequate increase in oxygen saturation in a cyanosed neonate, a congenital heart defect with ductal dependent lung perfusion must be assumed.
As innocent murmurs are unlikely in this age group, a heart murmur in a neonate is always suggestive of a congenital heart defect. Usually, stenosis of the semilunar valves or AV valve insufficiency present immediately after birth due to a loud systolic murmur, the typical VSD murmur in a large VSD, for example, can often be not auscultated until after the pulmonary resistance has dropped and the pressure gradient between the left and right ventricles increases. In addition, in many critical heart defects, there might be no indicative heart murmur at all (e.g., d-TGA simplex, coarctation of the aorta).
Arrhythmias often present in neonates without structural heart defects (i.e., atrial flutter, congenital AV block) and therefore are rarely the first symptom of a congenital heart defect. An AV block may occur in association with an l-TGA or heterotaxy syndromes. Supraventricular tachycardia due to accessory conduction pathways occurs more frequently with an Ebstein anomaly. The most common arrhythmia in a newborn is atrial flutter that requires immediate electrical cardioversion after diagnosis with adenosine but usually presents without additional defects.
The congenital heart defects that become symptomatic in neonates can be divided into five groups (Table 1).
Group | Examples |
---|---|
Cardiac defects with ductal-dependent systemic circulation (left heart obstructions) | Critical aortic stenosis, hypoplastic left heart syndrome, interrupted aortic arch, critical coarctation of the aorta |
Cardiac defect with ductal-dependent pulmonary circulation (right heart obstructions) | Critical pulmonary stenosis, pulmonary atresia with intact ventricular septum, pulmonary atresia with VSD, pronounced form of Tetralogy of Fallot, severe Ebstein’s anomaly, tricuspid atresia with pulmonary atresia or high-grade pulmonary stenosis |
Cardiac defects with parallel circulation | d-TGA—transposition of the great arteries |
Cardiac defects with complete intracardiac mixing of blood | Total anomalous pulmonary venous connection, univentricular heart |
Cardiac defects with a large left-to-right shunt symptomatic usually after 4–6 weeks | Large VSD, complete AVSD, large PDA, aortopulmonary window, Truncus arteriosus communis, univentricular hearts with unobstructed pulmonary blood flow |
Classification of congenital heart defects which become symptomatic in the neonatal period.
In a ductal-dependent defect survival depends on the persistence of a patent ductus arteriosus. In general, ductal-dependent systemic circulation must be distinguished from ductal-dependent pulmonary circulation. In patients with ductal-dependent systemic circulation, there is a high-grade obstruction of the structures of the left heart (mitral valve, aortic valve, arch and coarctation). To ensure sufficient systemic perfusion, the systemic circulation must be supplied with blood from the pulmonary circulation across the patent ductus arteriosus like in utero. In ductal-dependent pulmonary circulation, there is a high-grade right heart obstruction leading to cyanosis. Perfusion of the pulmonary circulation depends mainly on the blood supply from the aorta across the patent ductus arteriosus.
\nIn parallel circulations (d-TGA), survival depends on additional shunts (especially a sufficiently large atrial shunt) between the two circulations to enable mixing of the cyanosed and the arterialized blood.
\nIn cardiac defects with complete intracardiac mixing of blood, the resulting cyanosis is often only relatively mild; when excessive pulmonary blood flow due to the lack of pulmonary stenosis is often present simultaneously, this leads to pulmonary recirculation of the saturated blood. Heart failure usually develops as a result of the excessive pulmonary blood flow after 4–6 weeks.
\nBased on this principle, congenital heart defects with a large left-to-right shunt do not become clinically symptomatic until the age of about 4–6 weeks; at that time, the PVR has dropped and the shunt between the systemic and pulmonary circulation increases dramatically. If left-sided heart obstruction is, however, also present (e.g., VSD with CoA), the symptoms may develop as early as the first week of life.
As a standard of care, oxygen saturation should always be measured in children both preductally (right hand) and postductally (lower limb). If there is a defect with ductal-dependent systemic circulation, the (postductal) oxygen saturation measured in the feet may be lower than the (preductal) saturation in the right hand.
\nThe brachiocephalic trunk branches off from the aortic arch well before the ductus arteriosus; therefore, it is safe to assume that the saturation measured in the right hand is equivalent to preductal saturation (except in the rare cases of a lusoric artery).
As metabolic acidosis is the typical finding in severe heart failure and cardiogenic shock, routine (arterial) BGA is recommended on multiple occasions. In addition, all BGA should measure lactate as surrogate of cardiac output and thereby tissue perfusion.
As mentioned before, today echocardiography is the diagnostic method of choice in all patients with a presumed cardiac defect or impaired circulatory situation. ECHO allows an accurate diagnosis of all significant cardiac defects that become symptomatic in the neonatal period. As modern standard of care, every neonatal unit must have ECHO and support of a pediatric cardiologist available on a 24/7 basis.
In the time of ECHO, this test has only anecdotic relevance and lacks sensitivity and specificity. This test has been used to distinguish between cardiac or pulmonary central cyanosis. After breathing 100% oxygen for a few minutes, the cyanosis disappears or should be clearly reduced in pulmonary cyanosis and there is a relevant increase in arterial partial oxygen pressure. In cardiac cyanosis, the partial oxygen pressure should remain largely unchanged as the cardiac right-to-left shunt or inadequate pulmonary perfusion cannot be compensated by the administration of oxygen.
Today in any case, echocardiography examination is preferable to a hyperoxia test and must be available in every neonatal unit on a 24/7 basis.
All neonates with suspected cardiac defect should have a pulse and blood pressure measurement at all 4 limbs. If a difference in blood pressure between the right arm (preductal) and the lower limbs (postductal) is then manifest or the peripheral pulses in the lower limbs cannot be palpated, this is a hint and leading findings of coarctation of the aorta or an interrupted aortic arch. This examination is helpful to assess systemic circulation.
In a large patent ductus arteriosus, there may be no difference in blood pressure between the upper and lower halves of the body even with relevant coarctation of the aorta or interrupted aortic arch. The saturations, however, vary substantially.
According to the different anatomic variations and physiologic situation, there is a substantial difference in the management of these children. The treatment principles for the various groups of congenital heart defects are presented below and based on the pathophysiology, the specific treatments of the individual heart defects in the neonatal period are described in this context.
\nIn ductal-dependent systemic circulation, we should reestablish the prenatal circulation. Therefore, attempts must be made to provide as much blood as possible from the pulmonary circulation to supply the systemic circulation via the patent ductus arteriosus. As a result of this strategy, a saturation of 75–85% is adequate and saturations >85% that indicate excessive pulmonary blood flow should be avoided. The treatment principles of ductal-dependent systemic circulation are as follows:
\nProvide patency of the ductus arteriosus with a continuous prostaglandin E1 infusion (initial dosage 20–50 ng/kg/min, to be reduced after ECHO assessment; caveat: Apnoea).
Lower systemic vascular resistance:\n
By reducing afterload: i.e., with sodium nitroprusside infusion
If catecholamines are needed: Use preferably milrinone and/or dobutamine (vasodilatation effects); avoid vasoconstrictive effects of other catecholamines (dopamine, noradrenaline)
Increase pulmonary resistance, increase pulmonary artery pressure:\n
Avoid intubation, extubate early
Avoid additional oxygen
Aim for mild metabolic acidosis (pH 7.35)
Aim for mild hypoventilation (pCO2 around 60 mmHg)
In case of pulmonary edema caused by congestion and pulmonary overflow, give intravenous diuretics (1–2 mg/kg furosemide), ensure high PEEP (i.e., 10–15 cm H2O) and reduce prostaglandin E1 to a minimum (e.g., 10 ng/kg/min)
The administration of oxygen (SatO2 >85%) as a general measure and hyperventilation in children with ductal-dependent systemic circulation can lead to an acute decompensation of the hemodynamic situation.
The situation is reversed in ductal-dependent pulmonary circulation, but the prenatal situation should be achieved too. Again a saturation of 75–85% is adequate and saturations >85% should be avoided as they indicate inadequate pulmonary perfusion. The following measures can be useful to allow more blood to flow from the systemic circulation to the pulmonary circulation via the patent ductus arteriosus if needed:
\nSecure patency of the ductus arteriosus via a prostaglandin E1 infusion (initial dosage 20–50 ng/kg/min).
Lower pulmonary vascular resistance:\n
Aim for mild metabolic alkalosis (use buffering) (pH 7.45–7.5)
Adjust ventilation for mild hyperventilation (pCO2 around 35 mmHg)
Increase FiO2
Increase systemic vascular resistance and support systemic pressure by:\n
Noradrenaline infusion
Possibly also adrenaline infusion
Use volume more generously
Do not use dopamine
Maintain rather high dosage of prostaglandin E1.
Prostaglandin E1 is given to maintain patency or reopen the ductus arteriosus in neonates with ductal-dependent defect. Due to its short half-life, it must be administered continuously intravenous. The initial dosage in a patient with a nearly closed duct is between 50 and 100 ng/kg/min. Based on the actual effect, this dosage can be reduced gradually to a minimum of 5–10 ng/kg/min,
\nThe most common side effects are as follows:
\nApnea (administer in readiness for intubation)
Bradycadia
Vasodilatation (pulmonary and systemic), hypotension
Fever
Edema
(Cortical hyperostosis, periostitis only after long-term administration)
Practical tip: When a prostaglandin infusion is required, always a second venous access should be inserted to ensure safe prostaglandin administration immediately via other access if the first one is dislocated. The second access can also be used for volume substitution in case of acute hypotension.
The only example of this cardiac defect is a transposition of the great arteries (d-TGA) together with its variations. The management of this situation is described in the specific treatment section.
The different cardiac defects (i.e., univentricular hearts) in this group are also described in the following treatment section.
When the pulmonary resistance drops after the first 4–6 weeks of life, the left-to-right shunt and thereby pulmonary blood flow will increase dramatically. Consequently, heart failure may develop caused by increased volume load, which must be treated medically (diuretics, ACE inhibitors, beta blockers, possibly digoxin or cathecholamines) until corrective surgery is performed. As additional oxygen will lower the pulmonary resistance and increase excessive pulmonary blood flow, no additional oxygen should be administered.
The initial management of these children has some common features:
\nShock therapy, including intubation and ventilation (high PEEP (>10 cm H2O) if there is pulmonary edema)
Prostaglandin E1: initial dosage 50–100 ng/kg/min
Oxygen: avoid excessive administration, use PEEP to improve oxygenation. (note: oxygen lowers pulmonary resistance and thus increases pulmonary blood flow)
Use diuretics (furosemide), to manage pulmonary edema and lower preload
Use catecholamines (dobutamine, adrenaline, NOT dopamine), preferably milrinone depending on blood pressure and myocardial function. (If there is a subvalvular stenosis, catecholamines should be administered with particular caution due to a possible increase in the obstruction.)
Assess by ECHO and reduce afterload (e.g., sodium nitroprusside)
Aim for moderate metabolic acidosis (target pH 7.35)
Administer as little volume as possible; preferably only after cardiac function has recovered or is assessed to be stable in echocardiography
Due to the severe obstruction of the aortic valve, the left ventricular function usually is markedly impaired and cannot provide sufficient cardiac output for the systemic circulation which is supplied with blood from the pulmonary artery via the patent ductus arteriosus (i.e., prenatal situation). Left ventricular hypertrophy and possibly fibroelastosis have already developed in utero. This defect is often associated with other left heart obstructions (mitral stenosis, coarctation of the aorta, hypoplastic aortic arch—i.e., Shones complex). If a heart murmur is not already detected in the neonate, many patients with critical aortic stenosis present in severe cardiac shock. In addition, there is differential cyanosis.
\nIn critical AoS with PDA-dependent systemic circulation (prostaglandin infusion), a left-to-right shunt at the atrial level is necessary to allow mixing of the oxygenated pulmonary venous blood via the right atrium, the right ventricle, the pulmonary artery and then the patent ductus arteriosus. A balloon atrial septostomy (Rashkind maneuver) may be necessary, if the shunt at the atrial level is not large enough,
If suspected ensure prompt transfer to a pediatric cardiac center for interventional catheterization and performance of balloon valvuloplasty (method of choice) or surgical commissurotomy (rarely required); possibly carry out an emergency Rashkind maneuver if there is a restrictive foramen ovale and inadequate left ventricular function after balloon valvuloplasty.
In patients with critical CoA, the lower half of the body is supplied with deoxygenated blood from the pulmonary artery via the PDA (differential cyanosis). When the ductus arteriosus closes, dramatic hypoperfusion of the body distal to the aortic isthmus occurs. The left ventricle has now suddenly contract against the pronounced obstruction and rapid decompensation occurs. Associations with other left heart obstructions (bicuspid aortic valve) or a VSD are common.
Again organize prompt transfer to a pediatric cardiac center for surgical correction, which is generally attempted after the hemodynamic situation has been stabilized. In some special conditions (e.g., for patients in poor general condition or with necrotizing enterocolitis—NEC), primary interventional catheterization with balloon dilatation or implantation of a coronary stent may be indicated for stabilization until surgery.
There are different forms of an interrupted aortic arch and the perfusion of the lower half of the body depends however entirely on a patent ductus arteriosus (i.e., prostaglandin). A VSD is nearly always associated with this defect and other left heart obstructions occur occasionally. Again oxygen saturation should be measured preductally (right hand), as the preductal saturation reflects the situation of the perfusion and blood supply in the CNS and coronary arteries. The levels measured in the lower limbs correspond with pulmonary arterial saturation.
Prompt transfer to a pediatric cardiac center for surgical correction.
In patients with a hypoplastic left heart syndrome (HLHS), both the pulmonary and systemic systems are supplied by the right ventricle. Although there are four forms of HLHS (i.e., MA and AoA, MS and AoA, MS and AoS, MA and AoS with VSD), retrograde coronary perfusion takes place in all across the ductus arteriosus with mixed blood from the pulmonary artery and retrogradely across the coarctation and ascending aorta. Within the first few hours of life, the drop in pulmonary resistance together with the manifestation of a coarctation causes the blood from the pulmonary artery to flow primarily into the pulmonary circulation. Therefore, the systemic circulation—together with the coronary arteries—is increasingly less perfused. Severe heart failure develops, which if untreated usually results in shock. As a result, there is severe metabolic acidosis but due to pulmonary recirculation, the oxygen saturation is only moderately reduced. The higher the oxygen saturation is, the more the ratio of pulmonary to systemic perfusion changes are in favor of pulmonary over perfusion and systemic underperfusion. In addition, postnatal closure of the PDA enhances this fatal circulation with underperfusion of the systemic circulation and excessive pulmonary perfusion [9].
\nIt is important to note that oxygenated pulmonary venous blood from the left atrium can only reach the systemic circulation across a sufficiently large shunt to the right atrium (see above).
Shock treatment, including intubation and ventilation (but avoid ventilation if possible, as long as the pH is balanced); hyperventilation must be avoided
Prostaglandin E1: initial dosage 50–100 ng/kg/min
Avoid administering oxygen (additionally reduces pulmonary resistance and thus systemic perfusion), target saturation 70–85%
Administer some furosemide (1–2 mg/kg) to lower preload or for pulmonary edema
Catecholamine treatment is often required, but should be administered with restraint (can increase the myocardial oxygen consumption), give milrinoneor dobutamine if needed, do not use dopamine
Possibly reduce afterload (e.g., sodium nitroprusside)
For severe acidosis, large amounts of NaBic are often required to manage acidosis (doses up to 10 ml/kgbw of NaBic are common!)
Aim for moderate metabolic acidosis (target pH 7.35, avoid over-buffering)
As little volume as possible should be administered; preferably only after cardiac function has recovered or is assessed to be stable in echocardiography
If the atrial defect is restrictive (leading symptom: severe cyanosis, oxygen saturation <65%, seriously ill child), pulmonary congestion has developed and an emergency balloon atrial septostomy (Rashkind maneuver) may be needed.
\nThe patient should be transferred quickly to a pediatric cardiac center for surgery after stabilization (usually a Norwood procedure as the first step of three-stage Fontan palliation).
The initial treatment of this group of patients has some common features:
\nProstaglandin E1 infusion: initial dosage 50–100 ng/kg/min
Initially more generous oxygen therapy (lowers pulmonary resistance)
Initially more generous volume therapy (i.e., 20 ml/kg bw)
Try to achieve mild metabolic alkalosis (use over-buffering) (pH 7.45–7.5)
Possibly ventilation and mild hyperventilation (pCO2 around 35 mmHg)
Possibly use an increase in systemic resistance (noradrenaline)
A critical pulmonary stenosis is a high-grade obstruction of the pulmonary valve with subsequent hypoxemia. As the right ventricle cannot drain into the pulmonary circulation, secondary hypoxia occurs due to a right-to-left shunt across the foramen ovale/ASD. The musculature of the RV is severely hypertrophic and the RV and tricuspid valve may sometimes be hypoplastic. To ensure oxygenation, the pulmonary circulation is supplied with blood from the aorta via the PDA.
After diagnosis and prostaglandin infusion organize transfer to a pediatric cardiac center for interventional catheter balloon valvuloplasty.
In pulmonary atresia with intact ventricular septum, which can be judged as extreme form of pulmonary stenosis, the right ventricle cannot drain its blood normally to the PA. The majority of blood from the right ventricle either flows back into the right atrium due to tricuspid regurgitation. In addition in some cases, the right ventricle may be connected with the coronary arteries via myocardial sinusoids. In the latter case, the coronary arteries may have other problems and are stenotic so that coronary perfusion may depend on blood flow from the right ventricle (right ventricular dependent coronary circulation (RVDCC). Usually there is suprasystemic pressure in the right ventricle and the right ventricle is hypoplastictic various degrees. Again, the pulmonary circulation is supplied with blood from the aorta via the PDA to ensure oxygenation.
After stabilization, organize transfer to a pediatric cardiac center. In most cases, cardiac catheterization is needed to rule out myocardial sinusoids and coronary anomalies. In some cases, it is possible to open the right ventricular outflow tract by interventional catheterization or implant a stent into the PDA. Otherwise interim palliative surgery (opening the right ventricular outflow tract or aortopulmonary shunt) must be performed accordingly.
In tricuspid atresia, that may give an example for all univentricular heart defects, there is no continuity between the right atrium and ventricle, so the right atrium can drain into the left atrium only across a right-to-left shunt at atrial level. There are various forms of tricuspid atresia depending on the variations of obstructions of the right ventricular outflow tract or pulmonic valve. The RV is usually perfused from the LV across a VSD that is almost always present. The RV is hypoplastic to various extents. Oxygen saturation is identical in the aorta and pulmonary artery because of the complete mixing of blood.
\nFrequently stenosis and even atresia of the pulmonary artery occur and may have a negative effect on the blood flow to the pulmonary circulation. If there is atresia or a high grade stenosis of the pulmonary artery, perfusion of the lungs depends on a patent ductus arteriosus (see above). In addition, the great vessels can be in normal position or in transposition.
\nIf there is no pulmonary stenosis and blood flow to the pulmonary circulation is unobstructed, the main symptom that may develop later on is heart failure (tachypnea, hepatomegaly, pallor, possible pulmonary edema), but this constellation is much less common.
\nInitial treatment if there is no pulmonary stenosis (leading symptom: heart failure):
\nAnticongestive treatment (diuretics, milrinone, rarely catecholamines)
Restrictive volume therapy
Restrictive oxygen therapy
Transfer to a pediatric cardiac center should be organized. If there is a restrictive atrial shunt (rare), an interventional catheter balloon atrial septostomy (Rashkind maneuver) may be needed. If there is inadequate pulmonary perfusion, a palliative aortopulmonary shunt is placed. The separation of circulations is performed later as multistep procedure (Fontan procedure).
In tetralogy of Fallot, there is a typical combination of a large VSD with overriding of the aorta, a subpulmonary and pulmonary stenosis, often combined with supravalvular stenosis of various degrees and a marked hypertrophy of the right ventricle. Cyanosis is determined by the extent of the obstruction of the right ventricular outflow tract and thereby pulmonary blood flow. In most cases, this obstruction is only mild at birth, but becomes more significant during the first few weeks of life due to the increase in the infundibular stenosis. If there is pronounced stenosis of the right ventricular outflow tract (functional pulmonary atresia), the children may already develop symptoms with cyanosis or hypoxic spells even in the neonatal period. Hypercyanotic spells occur if there is a sudden increase in subpulmonary muscular obstruction of the RVOT (i.e., agitation) or an acute drop in peripheral vascular resistance (i.e., after feeding).
\nTreatment of a hypoxic-hypercyanotic spell:
\nImmediate sedation (e.g., ketamine IV 2–5 mg/kg, alternatively opiates, benzodiazepines)
Oxygen therapy
Increase in systemic resistance by\n
pressing the child’s flexed knee against the chest (“jack-knife position”)
if necessary infusion of vasoconstrictors (noradrenaline)
generous volume bolus (e.g., 20–50 ml/kg)
Compensation of metabolic acidosis by buffering
Possibly beta blockers (e.g., propranolol IV 0.01–0.1 mg/kg very slowly under monitor guidance)
Rapid transfer to a pediatric cardiac center is urgently needed. In most circumstances, interventional management can improve the hemodynamic situation (i.e., balloon dilatation of the pulmonary valve, stenting of the right ventricular outflow tract, stenting of a PDA). Only in few cases, early surgical correction is required today. In special situations (e.g., very small children), an aortopulmonary shunt is first placed as a palliative measure to ensure lung perfusion.
From the hemodynamic aspect, this disease is an extreme form of Tetralogy of Fallot. Pulmonary perfusion is, however, dependent on a patent ductus arteriosus (prostaglandin infusion) or aortopulmonary collaterals.
After stabilization with prostaglandin infusion, a rapid transfer to a pediatric cardiac center should be organized. In cases with only membranous valvular atresia, an attempt can be made to open the valve by interventional catheterization (or with stent placement). In addition placing a stent in the PDA may help to achieve catch-up growth of the pulmonary vessels, which are almost always hypoplastic. If this intervention is not possible, an aortopulmonary shunt is placed as surgical palliation. After catch-up growth of the pulmonary vascular system, a continuity between the pulmonary vessels and the right ventricle is created surgically later (e.g., with a valved conduit).
In Ebstein’s anomaly, there is apical displacement of the tricuspid valve into the right ventricle combined with moderate to severe tricuspid regurgitation and reduced flow from the small right ventricle to the pulmonary artery. The right atrium is markedly too massively dilated. A pronounced Ebstein’s anomaly can already be symptomatic in the neonatal period. Cyanosis occurs due to a right-to-left shunt at the atrial level caused by minimal antegrade flow to the pulmonary artery. In addition, the gross dilatation of the heart may compress the lungs and impair pulmonary function.
\nThe disease may often complicated by accessory pathways (Wolf-Parkinson-White syndrome).
\nBesides initial treatment stated above, in Ebstein’s anomaly:
\nIf there is heart failure, possibly catecholamines and diuretics
If there is supraventricular tachycardia, it should be terminated with a vagal maneuver, adenosine, amiodarone, possibly cardioversion
The goal of surgical treatment is to reconstruct the tricuspid valve and close the ASD. If there is insufficient lung perfusion, it may be necessary to place an aortopulmonary shunt. If there is pronounced hypoplasia of the right ventricle, the univentricular Fontan pathway may be the only option. The overall prognosis is unfavorable for children who become symptomatic already in the neonatal period. These children require urgent transfer to a pediatric cardiac center.
In d-TGA, there is parallel connection of the pulmonary and systemic circulations; the systemic venous blood is directed back into the aorta and the pulmonary venous blood is pumped back to the pulmonary artery. Survival is only possible if shunts between the two circulatory systems do exist. The most important is a patent foramen ovale or ASD as shunt at atrial level, so oxygenated blood can reach the systemic circulation via the right ventricle across this left-to-right shunt. A PDA has a favorable effect on oxygenation because PDA blood flow increases lung perfusion and as a result the volume load and pressure in the left atrium is increased, so the left-to-right shunt at atrial level increases and more oxygenated blood can reach the systemic circulation [10].
\nOxygen application may act indirectly by reducing pulmonary resistance and thus increasing pulmonary perfusion and thereby left atrial volume load and pressure (caution: uncontrolled administration of oxygen can also lead to closure of the ductus arteriosus when used without prostaglandin).
\nIn addition to improve mixing between the two circulations, especially in “poor mixers,” an attempt should be made to improve mixed venous saturation.
\nIf there is an associated large VSD, cyanosis is usually less pronounced.
\nInitial treatment:
\nProstaglandin E1 infusion: initial dosage 50 ng/kg/min
Generous volume therapy
Aim for mild metabolic alkalosis (over-buffering) (pH 7.45–7.5, lowers pulmonary resistance)
Oxygen therapy for severe cyanosis in neonates (caution: induces closure of the ductus arteriosus)
If possible avoid intubation, ventilation and relaxation (lowers oxygen consumption and therefore increases mixed venous saturation. On the other hand, ventilation increases the intrathoracic pressure, which can impair mixing of the blood)
Consider the improve cardiac output and thus mixed venous saturation by milrinone
Generous treatment of anemia (improves oxygen supply)
If there is a restrictive shunt at the atrial level, a bedside interventional catheter balloon atrial septostomy (Rashkind maneuver) should be performed as soon as possible before transfer to a pediatric cardiac center. The surgical standard treatment is an arterial switch operation (Jatene procedure) within the first 2 weeks of life.
In a truncus arteriosus communis (TAC), only one vessel (common trunk) arises from the heart. The systemic and pulmonary circulation and the coronaries are here supplied from this trunk only. A VSD is almost always present. Since the blood follows the path of least resistance and tends to flow into the pulmonary circulation, there is usually excessive pulmonary blood flow after the drop in pulmonary resistance between the second and eighth weeks of life. In this situation, clinical signs of heart failure are already present in the first weeks of life. Due to the significant pulmonary recirculation, there is often only astonishingly mild cyanosis, although the trunk vessel contains only mixed blood.
\nInitial treatment:
\nOxygen lowers pulmonary resistance and thus increases blood flow to the pulmonary circulation, leading to excessive pulmonary blood flow and increasing heart failure—therefore, use oxygen restrictively
Treatment of heart failure: diuretics, possibly catecholamines (dobutamine) or phosphodiesterase inhibitor (milrinone), afterload reducer (ACE inhibitor, possibly sodium nitroprusside)
If associated with an interrupted aortic arch: prostaglandin E1 infusion: initial dosage 50–100 ng/kg/min
Organize transfer to a pediatric cardiac center. The definitive correction with a Rastelli procedure is generally performed within the first weeks of life depending on the clinical signs of heart failure.
Depending on the location of the anomalous connection of the pulmonary veins, we distinguish between supracardiac, cardiac, infracardiac and mixed forms. Please note that an infracardiac total anomalous pulmonary venous connection is regularly associated with an obstruction at the connection site.
\nIn a total anomalous pulmonary venous connection, all pulmonary veins drain into the systemic venous system and oxygenated blood is guided from there into the right atrium. The perfusion of the systemic circulation thus depends on a right-to-left shunt at the atrial level that is necessary for survival.
\nIn a TAPVC without obstruction of the pulmonary vein, the hemodynamic situation is similar to that of a large ASD (volume overload of the right atrium, ventricle and pulmonary circulation).
\nInitial treatment:
\nTotal anomalous pulmonary venous connection with obstruction of the pulmonary vein:
\nOxygen therapy
Intubation and ventilation with a high PEEP (>10 cm H2O) for pulmonary edema
Lower PVR: hyperventilation, generous buffering (target pH 7.45–7.5), increase oxygen supply, possibly inhaled NO or prostacyclin IV
Diuretics, possibly catecholamines for low cardiac output (caution: catecholamines can exacerbate pulmonary edema)
A TAPVC with obstruction of the pulmonary vein is an absolute cardiac surgery emergency that must be surgically corrected immediately. Dilatation with or without stent implantation can treat the stenosis of the pulmonary vein in individual cases, so that the surgical repair can be performed after the child is stabilized.
\nIf there is a restrictive atrial shunt or if surgical correction is not possible immediately, an interventional catheter balloon atrial septostomy (Rashkind maneuver) may be considered.
In a complete atrioventricular septal defect (AVSD, AV canal), both segments of the ventricular and atrial septum in the region of the AV valves are absent and the development of the AV valves is also impaired. This malformation results in a large left-to-right shunt that increases when the pulmonary resistance drops within the first weeks of life. Children with a complete AVSD usually develop heart failure when the pulmonary resistance drops after 2–8 weeks of life. The situation can be complicated by (mainly systemic) AV valve insufficiency.
trisomy 21 is frequently associated with AVSD. All neonates with trisomy 21 must therefore have an ECHO examination at an early age.
Initial treatment:
\nAvoid oxygen (excessive pulmonary blood flow is increased)
Pharmacological treatment of heart failure: diuretics, ACE inhibitors, beta blockers, rarely catecholamines (possibly digoxin?)
The corrective surgery is generally performed at the age of 4–6 months and it may be necessary earlier if conservative heart failure treatment is unsuccessful.
The following remarks apply primarily to those patients that are transferred immediately after surgery from the surgical operating room and their early postoperative period in the pediatric cardiac intensive care unit (PCICU).
\nOne of the main requirements for providing good quality of care in a PCICU is to understand that the job of the intensive care physician starts far before the operated child is admitted to the PCICU. Detailed information on the case of the child is required in advance before the day of admission. The PCICU intensivist must be aware of and understand the hemodynamics of the cardiac defect (i.e., check the ECHO, cath data, etc.), possible complicating or concomitant diseases, the actual planned surgical repair or procedure and the usually possible perioperative and postoperative complications.
\nEvery intensive care physician should be familiar with the major steps of cardiac surgery in general and the specific steps and details of the case to be admitted. These steps include the whole process of surgery from opening the thorax and the mediastinum, thereafter arterial and venous cannulation for the cardiopulmonary bypass, initiation of cardiopulmonary bypass, cardioplegic arrest and finally, the restoration of cardiac function at the end of the operation including decannulation and closure of the thorax.
\nTo obtain this crucial understanding, every intensivist should visit the cardiac theatre on a regular basis and observe about 50 surgeries per year. In complex cases, the intensivist should work together in the time after decannulation or weaning of the bypass with the anesthetist before admission of the patient to the PCICU.
The majority of patients will be admitted on a planned and forseable basis. Before the patient is transferred to the PCICU, a careful and standardized preparation of the bed/place must be completed to avoid unnecessary misunderstanding and streamline the admission process. This preparation may vary from unit to unit but generally includes the following:
\nPreparation of the ventilation equipment, adjustment of the settings to the estimated patient-specific parameters, checking of the ventilation bag and mask, oxygen delivery, suction equipment and catheters. In addition, it must be determined by contacting the operating theatre or by assessment of the preoperative information whether iNO (nitric oxide) ventilation is required and possible with the ventilation equipment
Medication plan: The prepared medication plan should be tailored to the patients’ age and weight and include the medication and calculated dosages for the presumed standardized postoperative treatment (i.e., sedation, pain therapy, antibiotics, catecholamines, vasodilators, diuretics, fluid therapy and infusions). The perfusors and flushing solutions should be purged and primed before the patient is transferred to the PCICU
Monitoring: The bedside monitor is checked beforehand and the patient-specific alarms according to reference values for age and disease are set
Administrative tasks: Unit specific paperwork is prepared and an X-ray order for the first postoperative X-ray and laboratory order for the first laboratory tests should be prepared
In order to understand the physiology of the patient, a detailed handover from the different disciplines treating the patient during surgery is necessary. The checklist in Table 2 contains some common and useful questions that the intensive care physician should discuss with the surgeons, anesthesiologists and cardiac technicians/perfusionists at transfer. The information is crucial and may have direct impact on the subsequent PCICU management.
- What were the intraoperative findings? Compared to before? |
- What surgical technique was performed? Any problems? |
- What drainages were placed intraoperatively (e.g., pleural drainage, mediastinal drainage)? |
- What is the assessment of postoperative result? |
- Was an intraoperative transesophageal echocardiography performed and what were the findings (residual gradient, valve insufficiency, residual shunt, myocardial function)? |
- Did any intraoperative arrhythmias occur? How were they treated? |
- Did any intraoperative bleeding problems occur? How were they treated? |
- Tube size and brand, cuffed and uncuffed? |
- Ventilation settings (FiO2, tidal volume, rate, peak pressure and PEEP) |
- Central venous catheter: location of insertion, size |
- Arterial access: location, size |
- Was an LA or pulmonary artery catheter placed? |
- Anesthetics and cardiac medication used (cathecolamines, vasodilators, anti arrhythmics) and their dosages |
- Heparinization and current coagulation levels |
- Use of blood products (pack red cells, platelet concentrates, fresh frozen plasma) |
- Bypass time |
- Aortic cross clamp time |
- Cardiac arrest time |
- Minimum temperature during bypass |
- Was hemofiltration performed at the end of the bypass? |
Checklist for postoperative transfer.
Immediately after the patient is admitted to the ICU, the most important clinical parameters must be assessed by the admitting physician and the nurses involved to confirm that the patient is in a stable and safe situation:
\nRespiration: Is the chest moving? How are thorax/chest movements? Symmetrical lung expansion? Adequate expansion? How is the Oxygen saturation? FiO2?
Circulation: Palpation of peripheral pulses (femoral, brachial), visual check of pressure parameters on the monitor (arterial blood pressure, CVP, if inserted pulmonary artery pressure or LA pressure) and check of capillary filling time (normal<2–3 s)
Diuresis: Is the urine bag filled? How much? Is the bladder filled despite urine catheter? Does the urine look clear or hemolytic? Does the patient appear edematous (puffy) or rather dehydrated?
Bleeding: Are the drains connected to suction? How much is in the bag and how quick is it filling? Are the secretions dark red (venous blood), bright red (arterial blood), yellowish or clear (serous), warm (fresh) or cold (older)?
Neurology: is the patient sedated/anesthetized, what is the status of the pupils, are there spontaneous movements and is the patient breathing against the ventilator?
Body temperature
Assessment of catheters, lines and cables inserted
During this gross examination to assess the patient’s stability, the patient is connected to the bedside monitor system and other equipment. The arterial and central venous accesses are connected with the pressure transducers, set to zero and activated again. The patient is also connected to the ventilator and the drainages set to suction (in general, the suction pressure is set at around 15 cm H2O). In addition, the external pacemaker is checked for proper function.
\nIn parallel, the first blood samples are taken and include an arterial and central venous blood gas analysis, an ACT and a survey of different pathology markers to asses organ function. The first blood gas analysis including electrolyte status provides information on the ventilation situation, the hemodynamic status (lactate, central venous saturation) and electrolyte metabolism (especially potassium). A standard limb ECG is then recorded, a chest X-ray arranged and finally, an initial exploratory echocardiography (ECHO) performed as a standard in every patient.
As capillary leak is a normal reaction to bypass and the subsequent inflammatory process induces edema of all organs, the amount of free water intake should be limited postoperatively. Therefore, fluid intake is ideally reduced to 30–50% of the normal maintenance on the first postoperative day and then increased day by day to 75 and finally 100% on the following days.
\nPatients, however, who underwent cardiac surgery without cardiopulmonary bypass (e.g., resection of an aortic coarctation, PDA ligature) do not require any restriction of postoperative fluid intake.
\nAs soon as the children are able to drink, oral fluid intake should not be restricted any more.
The majority of patients are ventilated after cardiac surgery when they arrive in the PCICU. Pulmonary function is affected by a large variety of preoperative, intraoperative and postoperative factors. Important examples to be considered are listed below:
\nPreoperative factors:\n
Preexisting excessive pulmonary blood flow (wet lung, congestion)
Preexisting pulmonary hypertension (left-to-right shunt)
External compression of the airways, for example, due to vascular rings or prominent pulmonary arteries
Intraoperative factors:\n
Atelectasis due to surgical manipulation in the thorax or lack of ventilation during the bypass
Edema development due to the effect of cardiopulmonary bypass and SIRS\n
Trauma of the lung
Postoperative factors:\n
Swollen mucosa (SIRS)
Atelectasis
Lung edema as a result of a postoperative increased lung perfusion. Typical examples are after a shunt procedure or operative opening of circulation in the lungs in pulmonary atresia or severe stenosis (“reperfusion edema”)
Impaired respiratory mechanics due to postoperative diaphragmatic paresis
Pain-related reduction in respiratory capacity (surgery drains)
Respiratory depression caused by drugs
Pneumothorax, pleural effusions\n
Bleeding through MAPCAS
Volume-controlled ventilation is the ventilation of choice in every cardiac patient after cardiac surgery. In many ventilators, a setting with a pressure control combination (i.e., PRVC-mode) can be chosen. Hereby markedly, lower rates are usually used (e.g., 20/min for neonates) in the sedated patient. The tidal volume is usually set to 10–15 ml/kg. A relatively long inspiration time is usually selected initially. The PEEP is around 5–10 mmHg and an FiO2 value is selected at which oxygen saturation of over 95% can be achieved. When the patients waking up, the volume controlled mode is combine with a SIMV mode.
\nIn spontaneous breathing patients, the following values can be used as references for the age-specific respiratory rate:
\nNeonates: 40/min
Infants: 25–30/min
Toddlers: 25/min
School-age children: 20/min
Adolescents: 15/min
Again, in the controlled situation, the rate settings used are much slower.
\nThe following situations are important variants from these initial settings of the ventilator:
\nCardiopulmonary bypass reduces the capacity of the immune system to act against bacterial infections and so postoperative antibiotic prophylaxis is always given for children after cardiac surgery. The antibiotics used and the duration of antibiotic treatment are, however, subject of some controversy. First or second generation cephalosporins are frequently used, for example, cefazolin 30 mg/kg/dose every 8 hourly. For an uncomplicated postoperative course, many centers carry out antibiotic prophylaxis for 2–3 days (6–9 doses, until the drains are out) although hardly any evidence-based data for this procedure are available. For patients with an open sternum or peritoneal dialysis or ECMO, no additional management is required but prolonged treatment is often used in many centers. Antibiotic prophylaxis is then continued for 24 h post-chest closure or ECMO/PD removal.
In most centers, a combination of an opiate (morphine, fentanyl) and a benzodiazepine (midazolam) is administered intravenously continuously in the initial postoperative period. Propofol is often used in older children who are sedated for only a short period. No time (2–3 days) or dose (3–8 mg/kg/h) limitation applies in these cases. Lactate levels should be checked on a routine basis.
Surgery itself and the drains in the body after surgery is painful procedure. To reduce postoperative pain, a fixed and standardized combination of non-steroidal analgesics (i.e., paracetamol, ibuprofen) and opiates (morphine, fentanyl) is usually used for analgesia for the first 2–3 days. Patient-controlled analgesia with a PCA pump is also applicable for older children (who can already play a video game).
Kidney function nearly always deteriorates in patients who have undergone cardiac surgery. The use of cardiopulmonary bypass leads to renal impairment and intraoperative fluid loading and inflammatory reactions that result in fluid retention. A negative fluid balance is therefore targeted postoperatively.
\nUrine excretion reflects a combination of cardiac function and cardiac output in combination with kidney function. In general, a urine excretion of at least 2 ml/kg/h after cardiac surgery is a minimum to ensure adequate fluid balance. Patients most often have a combination of pre-renal kidney failure (low cardiac output, capillary leak, volume deficit) in combination with the direct effects of SIRS on the kidney itself. In addition, a low systemic blood pressure and, in case of ascites, a high intra-abdominal pressure leads to a low perfusion pressure in the kidneys (aggressive drainage of ascites). Other less common examples of renal kidney failure are renal vein thrombosis or iatrogenic kidney damage (aminoglycosides, cyclosporin A). Post-renal kidney failure can be caused by obstructions in the region of the efferent urinary tract (e.g., obstruction of the urinary catheter or the urethra) or simply by increased intra abdominal pressure caused by capillary leak and ascites.
\nSuitable diuretics in the postoperative phase are primarily loop diuretics (Furosemide, ethacrynic acid). They are administered as a bolus or as a continuous infusion if the response is inadequate. The combination with theophylline sometimes enhances the effect. If excretion is insufficient or the fluid balance is clearly positive, peritoneal fluid drainage, or peritoneal dialysis should be initiated early.
Typical postoperative problems and their most common causes are summarized in Table 3.
Problem | Common causes |
---|---|
Blood pressure too high | Pain, fear, catecholamines, excessive fluid volume, result of the abrupt drug discontinuation (beta blockers, ACE inhibitors); typical postoperative problem after correction of an aortic coarctation. Rare causes: cerebral seizures, hypoglycemia (counter regulation) |
Blood pressure too low | Hypovolemia, low cardiac output: limited myocardial function, pericardial effusion, arrhythmia (junctional ectopic tachycardia, AV block), excessive drainage loss, hemorrhage, excessive diuresis; vasodilators, anaphylaxis, sepsis, shock, pneumothorax |
Central venous pressure (CVP) too low | Fluid deficit (excessive drainage losses, hemorrhage, excessive diuresis, volume intake too low) |
Central venous pressure (CVP) too high | Tense/stiff patient (reaction to wake up, insufficient sedation in ventilation patients); impaired right ventricle function. In patients with univentricular heart, a high CVP suggests poor systemic ventricular or a relevant AV valve regurgitation. Other causes are a pericardial tamponade or pneumothorax |
Arterial saturation too low | Atelectasis, hypoventilation, technical problems with the ventilation device, disconnected/obstructed tube, pneumothorax, pleural effusion, pneumonia, pulmonary edema, pulmonary hemorrhage, secretion, right to left shunt |
Arterial saturation too high | In patients with univentricular hearts, saturation over 85% suggest an imbalance between pulmonary and systemic perfusion: excessive blood flow to the lungs and diminished supply to the systemic circulation |
Bradycardia | Sinus bradycardia, AV block |
Tachycardia | Narrow QRS complexes: sinus tachycardia, supraventricular tachycardia, JET Wide QRS complexes: ventricular tachycardia |
Increase in lactate | Poor systemic perfusion, seizures, gut ischemia |
Typical postoperative problems and the most common causes.
There is a variety of factors that can result in myocardial dysfunction and subsequent low cardiac output postoperatively. Typically, they include an inflammatory reaction to cardiopulmonary bypass, myocardial ischemia and inadequate myocardial function as a result of the intraoperative clamping of the aorta, intraoperative hypothermia, a reperfusion edema, or if a surgical procedure was performed using a ventriculotomy—direct myocardial damage, coronary ischemia, inadequate cardioplegia, mechanical alteration, or an infection.
\nTypical clinical signs of low cardiac output are as follows:
\nTachycardia
Oliguria
Delayed capillary filling time (>3–4 s)
Hypotension
Decreased pulse pressure
Reduced mixed venous saturation (Note: a difference between arterial and mixed venous saturation not <20–25% suggests sufficient cardiac output and adequate oxygen supply)
Metabolic acidosis (BE less than −5)
High lactate level (>3 mmol/l)
The treatment of low cardiac output has to focus on the underlying causes which should be eliminated if possible. The following measures depending on the hemodynamic situation are commonly used as follows:
\nVolume substitution (in case of hypovolemia)
Inotropic support (catecholamines (i.e., adrenaline, dobutamine), phosphodiesterase inhibitors, intravenous calcium)
Afterload reduction (sodium nitroprusside, phosphodiesterase inhibitors)
Consider hormonal therapy for hypotensive resistance to epinephrine and vasopressors: cortisol for suspected adrenal insufficiency, IV or oral triidothyronine (T3) for euthyroid sick syndrome (low T3 levels with LCOS symptoms)
Chronotropic support (pacemaker therapy, positive chronotropic drugs)
Treatment of arrhythmias (amiodarone)
Ventilation strategy
Reduction in oxygen consumption (sedation, cooling)
Mechanical circulatory support (ECMO, LVAD)
Based on the underlying anatomy and pathophysiology, many patients may have a significant elevation of pulmonary pressures or pulmonary vascular resistance before surgery. Typical heart defects for this are those with high flow and pressure driven left-to-right shunt defects (large VSD, AVSD, Truncus, etc.) and those with unrestricted flow over a long period (i.e., >6 or 12 months of age). Postoperatively, there may be a rapid and critical increase in pulmonary arterial pressure or pulmonary vascular resistance in certain situations (i.e., agitation, external stimulation such as suctioning, pain, etc.). The result of a rapid increase in PVR is a standstill of the trans-pulmonary blood flow with secondary congestion in the right atrium (high CVP) and ventricle and drop in pressure in the left atrium and ventricle (low CO and BP). Ultimately, cardiac output collapses and the coronaries are not perfused. The following patients are at a particularly high risk for this type of crisis:
\nPatients with already increased pulmonary vascular resistance preoperatively (primary pulmonary hypertension)
Neonates within the first week of life
Patients with pulmonary venous hypertension (e.g., within the context of a total anomalous pulmonary venous connection or mitral stenosis)
Older children with a still uncorrected high flow and pressure shunt defects that led to an increase in pulmonary vascular resistance (e.g., complete AV canal, large VSD, truncus)
The following factors may increase pulmonary vascular resistance:
\nHypoxia
Acidosis (pH <7.3, BE less than −5)
High partial pressure of carbon dioxide (paCO2 >50)
Polycythemia
Atelectasis
Agitation
The following factors may reduce pulmonary vascular resistance:
\nOxygen administration
Alkalosis
Hyperventilation
NO inhalation (nitric oxide)
Recruitment of atelectatic lung segments
Prophylaxis of a pulmonary hypertensive crisis is crucial, the acute management as well as the prophylaxis of a pulmonary hypertensive crisis includes the following measures:
\nSufficient analgesia and sedation or relaxation for 1–2 days
Oxygenation (paO2 >150)
Optimizing the ventilation (adequate PEEP)
Slightly alkalotic pH level (target pH 7.4–7.5) and mild hyperventilation (paCo2 30–35)
Pharmacological vasodilators (NO, iloprost, prostacyclin)
Avoidance of unnecessary manipulations such as too frequent suctioning
Cardiac defects or surgery-specific postoperative problems and complications are summarized in Table 4.
Cardiac defect/operation | Specific early postoperative problems and complications |
---|---|
ASD closure | Sinus node dysfunction, left heart failure/pulmonary edema in older children and adults |
VSD closure | Pulmonary hypertensive crisis, complete AV block, JET, residual shunt |
AV canal correction | Pulmonary hypertensive crisis, complete AV block, JET, AV valve stenosis or incompetence |
PDA ligation | Injury to the recurrent laryngeal nerve (vocal cord paralysis) or the thoracic duct (chylothorax), accidental ligation or injury to surrounding vessels (especially left pulmonary artery, aorta |
Truncus arterious correction | Pulmonary hypertensive crisis, truncus valve stenosis or incompetence, right ventricular dysfunction |
Aortopulmonary window (correction) | Pulmonary hypertensive crisis, coronary ischemia |
Anomalous pulmonary venous connection (correction) | Pulmonary hypertensive crisis, atrial arrhythmia, residual stenosis of the pulmonary veins or pulmonary vein anastomosis with the left ventricle, high left ventricular filling pressure due to the relatively small left atrium and ventricle |
Fallot correction | Right ventricular diastolic dysfunction (poor compliance of the hypertrophic ventricle), JET, complete AV block, residual pulmonary stenosis, residual VSD, pulmonary insufficiency after a transannular patch |
Pulmonary atresia with intact ventricular septum | Right ventricular dysfunction, myocardial ischemia due to right ventricle dependent coronary circulation, circular shunting due to creation of an aortopulmonary shunt and opening of right ventricular outflow tract |
Aortic stenosis correction | Residual stenosis, disruption of left ventricular diastolic function, aortic insufficiency, AV block |
Ross procedure | Coronary ischemia |
Konno procedure | Coronary ischemia, obstruction of the right ventricular outflow tract, arrhythmias (e.g., AV block), mitral regurgitation |
Subaortic stenosis (resection) | Residual stenosis, mitral valve injury, (ventricular) arrhythmia, AV block |
Coarctation of the aorta (resection) | Residual obstruction, paraplegia, post-coarctectomy syndrome, unmasking an aortic valve stenosis, injury to the recurrent laryngeal nerve, chylothorax |
Interrupted aortic arch (correction) | Residual obstruction, compression of the left main bronchus by the aorta, injury to the recurrent laryngeal nerve, chylothorax |
Mitral stenosis correction | Pulmonary hypertensive crisis, residual stenosis, mitral regurgitation, left ventricular dysfunction |
Creation of an aortopulmonary shunt | Imbalance between systemic and pulmonary perfusion, shunt leak, shunt thrombosis, pulmonary edema, coronary ischemia |
Pulmonary artery banding | Cyanosis, insufficient banding (excessive pulmonary blood flow), Qp-Qs mismatch |
Norwood procedure | Low cardiac output, imbalance between systemic and pulmonary perfusion, residual obstruction of the aortic arch, AV valve insufficiency, SIRS |
Superior cavopulmonary anastomosis (Glenn, Hemifontan) | Cyanosis, hypertension, edema/congestion of the upper half of the body, Chylothorax |
Fontan completion | Ascites, pleural effusions, edema, cyanosis, low cardiac output, arrhythmias |
TGA (switch operation) | Coronary ischemia, left ventricular dysfunction, neo aortic insufficiency, peripheral pulmonary stenosis |
TGA (Mustard/Senning atrial baffle procedure) | Pulmonary or systemic venous obstruction, atrial arrhythmias |
Bland-White-Garland syndrome (correction) | Myocardial dysfunction, mitral regurgitation |
Specific early postoperative problem and complications (modified from Schwartz and Millar 2009 in Roger’s Handbook of Pediatric Intensive care).
The large group of heart defects with a univentricular physiology may pose great challenges to postoperative intensive care in the PCICU. These patients include those with a hypoplastic left heart syndrome, tricuspid atresia, or a double inlet left ventricle. The most important principles in the postoperative treatment of these patients are presented below. As an example, the three-stage surgical procedure for patient with a hypoplastic left heart syndrome is explained. In general, palliation in a Fontan procedure is made with the goal of achieving complete separation of the pulmonary and systemic circulation to eliminate cyanosis. The lungs are perfused passively from the vena cavae without any pumping chamber in between. The single ventricle supplies only the systemic circulation and thereby has a reduced volume load.
\nThe three stages are as follows:
\nNorwood procedure or Damus-Kaye-Stansel procedure with a shunt
Upper cavopulmonary anastomosis (Glenn procedure, “hemi Fontan”)
Total cavopulmonary anastomosis (Fontan procedure)
The Norwood procedure is the first step for patients with a hypoplastic left heart syndrome toward separation of the circulatory systems by a Fontan procedure. There are several modifications of this surgical procedure (classical Norwood, Norwood-Sano-procedure). The principal goal is to form a neo-aorta from the pulmonary artery and the hypoplastic aorta that can supply the systemic circulation with blood without a pressure gradient (i.e., unobstructed systemic blood flow). To achieve this, the pulmonary artery and the hypoplastic aorta are anastomosed distal to the valves. Additional patch material is usually required for the reconstruction of the aortic arch and excision of the coarctation. In this manner, a strong vessel for systemic perfusion is created. The pulmonary artery is transected shortly before the pulmonary artery bifurcation and in most cases, pulmonary perfusion is ensured via an aortopulmonary shunt or Sano shunt (placement of a conduit through right ventricular to pulmonary artery).
\nTo achieve the unobstructed inflow to the heart and outflow from the pulmonary veins, an atrial septectomy is also performed. There is a balance between the pulmonary and systemic circulatory systems when arterial saturation is between 75 and 85% (Qp/Qs = 1).
\nTypical problems after a Norwood procedure are low cardiac output, capillary leak caused by SIRS and hypoxemia.
\nAs a typical result of the long bypass time required or even prolonged circulatory arrest, a systemic inflammatory response syndrome (SIRS) of various degrees occurs in these neonates. As a consequence, myocardial function is usually markedly impaired so that a certain and often higher amount of catecholamine support is always needed postoperatively. Other possible causes of inadequate systemic perfusion are increased pulmonary perfusion at the expense of systemic perfusion (Qp/Qs >1; leading symptoms: arterial saturation>85%, tachycardia, hypotension, oliguria, metabolic acidosis). To manage this situation, an attempt is made by reducing the afterload of the systemic circulation and increasing pulmonary resistance. AV valve insufficiency or arrhythmias can also cause or deteriorate low cardiac output.
Hypoxemia (i.e., saturation <70%) can be the result of an imbalance between pulmonary and systemic circulations to the detriment of the pulmonary circulation—for example, in an obstruction of the aortopulmonary shunt or increased pulmonary resistance.
\nOther causes are typical pulmonary problems such as atelectasis, a pleural effusion, edema, or pneumonia. Peripheral cyanosis occurs with low cardiac output or increased oxygen consumption (leading symptom: reduced systemic venous saturation).
The aim of a superior cavopulmonary anastomosis is to allow passive blood flow from the upper half of the body into the pulmonary circulation. The superior vena cava is anastomosed in an end-to side manor with the pulmonary artery and thereby the systemic venous blood from the upper half of the body then flows passively to the lungs without an intermediate pumping chamber and is oxygenated there. The systemic venous blood from the lower half of the body does not reach the lungs, but is mixed with the pulmonary venous blood in the heart and pumped into the systemic circulation. The systemic circulation thus contains mixed blood. The saturation of these children is usually about 80–85%.
\nThis step leads to a complete hemodynamic unloading of the univentricular heart as the pulmonary circulation and systemic circulation are now connected in series. The Qp/Qs ratio is then 0.6–0.7; oxygen saturation is 80–85%. In comparison with older children, the head and upper limbs in young children are relatively large and therefore, the overall ratio of pulmonary perfusion is still higher in younger children. The percentage of systemic venous blood from the upper half of the body, that reaches the lungs via the cavopulmonary anastomosis and is oxygenated there, is correspondingly higher.
\nTypical postoperative problems are increased pressure in the superior vena cava, hypertension and hypoxemia.
\nIn a superior cavopulmonary anastomosis, elevated pressure in the superior vena cava suggests an obstruction in the area of the cavopulmonary anastomosis or pulmonary circulation or elevated pulmonary vascular resistance.
\nThe difference in pressure between the superior vena cava and atrium (transpulmonary gradient) should be <10 mmHg. A high pressure in the superior vena cava can restrict cerebral outflow and lead to marked edema in the upper half of the body (superior vena cava syndrome).
\nAfter this operation, patients should be positioned with the upper body elevated (about 45°, half sitting position). Elevated intrathoracic pressure from mechanical ventilation additionally hinders passive blood flow from the superior vena cava into the pulmonary circulation and patients should therefore be quickly extubated.
Temporary hypertension during the first few postoperative days is not unusual in these patients. The elevation of intracranial pressure that is necessary to maintain adequate cerebral perfusion pressure may be one reason. Aggressive lowering of the blood pressure should therefore be avoided but normal arterial pressures should be obtained.
Saturation levels below 75% following a superior cavopulmonary anastomosis can be caused by many reasons all resulting in a reduction in pulmonary perfusion. This may be due to an obstruction in the area of the anastomosis or pulmonary vessels. Another possible explanation is that blood from the upper half of the body is conducted past the alveoli, for example, if there are venovenous collaterals (connections between the systemic and pulmonary veins), the azygos vein was not ligated by the surgeon, a left sided superior vena cava has reopened or arteriovenous collaterals (connections between the pulmonary arteries and veins) have gained importance.
\nIn the early postoperative phase, arterial saturation can often be improved by attempting mild hypoventilation. Slightly elevated pCO2 (>50 mmHg) causes vasodilatation of the cerebral vessels, so more blood flows to the brain. Since this allows relatively more blood to reach the upper half of the body, more blood is conducted through the SVC and into the lungs and becomes oxygenated. In addition, the blood can also be slightly alkalized by administering sodium bicarbonate (target pH >7.4).
In a Fontan procedure (total cavopulmonary anastomosis), the pulmonary and systemic circulation are finally completely separated by anastomosing the inferior vena cava also with the pulmonary circulation. A tunnel is created that connects the inferior vena cava with the pulmonary artery. This tunnel may pass either through the atrium (intracardiac Fontan) or alternatively outside the heart (extracardiac tunnel). It should be standard to leave a small shunt between the Fontan tunnel and the atrium (i.e., Fontan fenestration) that functions as an overflow (right-to-left shunt) if the resistance in the pulmonary circulation is too high and not all of the systemic venous blood can enter the pulmonary circulation. This may have the disadvantage of mild hypoxemia but the positive effects (improved systemic circulation, decompression of the venous side, less ascites, edema, etc.) clearly overweigh the disadvantage of lower saturations.
\nWhen the Fontan circulation is completed, all of the systemic venous blood (exception: coronary sinus) flows passively into the pulmonary circulation without passing through a pumping ventricle. The oxygenated blood is then pumped into the systemic circulation by the univentricular heart.
\nTypical postoperative problems are low cardiac output, hypoxemia, effusions, arrhythmias and thrombosis.
\nIn Fontan patients, low cardiac output can often occur due to low preload (hypovolemia), increased pulmonary resistance, or an obstruction in the area of the systemic venous outflow (tunnel stenosis, anastomosis stenosis). Therefore, higher volume requirements are often necessary in these patients. In addition, poor ventricular function or AV valve insufficiency and arrhythmias can also cause low cardiac output.
As the completion of the Fontan procedure require surgical manipulation at the atrium and the area of the sinus node, atrial arrhythmias may occur and sinus node dysfunction is typical. A pacemaker (atrial stimulation) sometimes becomes necessary.
Cyanosis can be the result of a relevant right-to-left shunt across a tunnel fenestration. In addition, the usual pulmonary problems (i.e., pleural effusion, atelectasis, pneumonia) can also lead to hypoxemia. Reduced pulmonary perfusion, caused by arteriovenous or venovenous collaterals can also cause hypoxemia in Fontan patients.
Pleural effusions and ascites are common immediately after surgery. They can be the result of elevated venous pressure and volume load required and may lead to considerable postoperative complications.
Based on the low flow in the Fontan circuit, these patients are at an increased risk of developing venous thrombosis. This risk is increased especially if there is low cardiac output. Most centers therefore recommend lifelong anticoagulation for Fontan patients. There is, however, no uniform opinion with respect to the duration or the form of anticoagulation (vitamin K antagonists or platelet aggregation inhibitors). While many different anticoagulation regimens are used in small children (no anticoagulation, aspirin, warfarin), there is a general consensus that anti-coagulation is obligatory in patients after puberty.
Parts of this book chapter are similar to a recent publication of the third author [11]. Based on the content of the scientific information, this is, however, current state-of-the-art knowledge and medical management; therefore, similarities in the text are logical necessity.
Abiotic stress factors such as extreme temperatures, drought, salinity, heavy metals, xenobiotics have been considered as potential threats for agricultural productivity. To cope with abiotic stress, plants can initiate a number of molecular, cellular, and physiological changes to respond and adapt to such stresses. Stress-tolerance of plants involves the activation of cascades of molecular networks leading to expression of stress-related enzymes.
The accumulation of heavy metals in the plant is accompanied by damage to the structural components and an imbalance of various metabolic processes in the cells, which leads to disruption of plant growth and development. Plants have evolved a number of mechanisms to adapt to increasing concentrations of metal ions. These include the immobilization, exclusion, chelation, and compartmentalisation of metal ions.
The toxic action of heavy metals can produce excessive reactive oxygen species (ROS). Glutathione and GSH related enzymes such as GSH reductase, GSH peroxidases and glutathione S-transferases are fundamental parts of the antioxidant defense system in the cells to scavenge ROS and electrophilic organic molecules as well. The significance of plant thiols and glutathione
A number of metal-binding ligands have now been recognized in plants [1]. Polypeptide ligands include the metallothioneins (MTs), small, gene-encoded, cysteine-rich polypeptides, and the phytochelatins (PCs), which, in contrast, are enzymatically synthesized are effective metal binding ligands have been identified. Recent advances in understanding the role, biosynthesis and protective action of phytochelatins and metallothioneins as metal-binding ligands in heavy metal detoxification are reviewed.
Proteinogenic amino acid proline protects cell from environmental stress factors by several protective mechanisms such as osmoprotectant, acting as chemical chaperone by stabilization of proteins and antioxidant enzymes, chelation of metals, scavenging ROS, balancing the intracellular redox homeostasis (NADP+/NADPH ratio, GSH pool) and participating in cellular metabolic signaling. Proline accumulation has been observed in response to environmental stress in a variety of living organism including plants.
Reactive electrophile species oxylipins exhibit protective action under toxic concentration of pollutants by activation of detoxification processes. The less studied oxylipin signaling in plant stress response will be detailed as an important factor in plant adaptation to stress by heavy metal pollutants.
The accumulation of heavy metals in plant organs results in the damage of the structural components and disruption of cell metabolic processes leading to plant growth retardation. The toxic action of heavy metals can produce excessive reactive oxygen species (ROS). Glutathione and GSH related enzymes such as GSH reductase, GSH peroxidases and glutathione S-transferases are fundamental parts of the antioxidant defense system in the cells to scavenge ROS and electrophilic organic molecules as well (Figure 1).
Biosynthesis of GSH and GSH/GSSG redox system with related enzymes such as glutathione peroxidase (GPX) and glutathione reductase (GR) as well as glutathione S-transferase.
The most abundant biological thiol the tripeptide glutathione (GSH, γ-Glu-Cys-Gly) is a low molecular weight, water soluble compound that is ubiquitous in most plant tissues and has a key function in stress management. Besides the ROS detoxification, GSH also participates in detoxication of methylglyoxal and electrophilic xenobiotics [2]. As a component of the glutathione-ascorbate (AsA-GSH) cycle GSH has a key role in H2O2 detoxication. GSH is used as co-factor by a) various peroxidases in detoxication of peroxides formed in the reaction of oxygen radical with biological molecules and b) by glutathione S-transferases (GST) to conjugate GSH with endogenous substances and xenobiotics. Interaction of GSH with thioredoxin systems fine-tune photosynthetic and respiratory metabolism by modifying the sensitive protein Cys residues [3]. GSH is a substrate of phytochelatin synthase and oligomeric GSH products phytochelatins (PCs) can effectively sequester heavy metals by complexation alleviating metal stress of plants [4]. Interaction of GSH with known signaling molecules such as salicilic acid, jasmonic acid and ethylene can be important in treatment of plant biotic stress [5].
GSH biosynthesis is two-step pathway mediated by γ -glutamylcysteine synthase (γ-ECS) and glutathione synthase (GSHS) enzymes using 2 molecules of ATP (Figure 1). The first step occurs mainly in the chloroplast while the second step predominantly takes place in the cytosol [3, 6]. GSH produced in the cytosol can be transported directly to other cellular organelles by glutathione transporters [7].
The GSH redox state in plants, particularly in leaves is normally very stable but is extremely sensitive to oxidative stress. In the absence of stress, in leaf tissues measurable GSH: GSSG ratios typically around 20:1 [8]. Conversion of the reduced GSH into oxidized glutathione or glutathione disulfide (GSSG) can occur under stress conditions. Non-enzymatic reactions of GSH with ROS species such as 1O2, O−2, OH, H2O2 and O22− convert the reduced GSH to the oxidized form (GSSG, glutathione disulfide) [9, 10]. Glutathione reductase (GR) and glutathione peroxidase (GPX) enzymes in conjuction with AsA-GSH cycle are responsible for the balanced state of GSH/GSSG and GSH homeostasis [11].
Plethora of information on alteration of plant GSH pool and GSH/GSSG redox system as a results of heavy metal stress are available. Elevated levels of GSH have been observed in various plant species with increasing Cd concentration. But depletion of GSH in roots of variety of species under cadmium and lead stress has also been reported [12]. In two genotypes of
Toxic action of heavy metals seemed to induce the expression of genes encoding γ -glutamylcysteine (γ-ECS) and glutathione synthase (GSHS) enzymes by enhancing GSH levels. Moreover, GSH can efficiently influence coordination of metals to the active sites of affected enzymes preserving their activity [16].
Glutathione reductase (GR) is a flavo-protein oxidoreductase mediates the reduction of GSSG to GSH using NADPH as an electron donor. GR is predominantly located in chloroplasts but some isoforms were also detected in mitochondria and cytosol [17]. GR activity secure the redox potential of cells at highly reduced GSH/GSSG and AsA/DHA ratios under regular and oxidative stress conditions. Biotic and abiotic stress factors including toxic metals were found to influence GR activities in plants [17, 18]. Under Cd stress GR activities were increased in sugarcane callus cultures in time- and concentration-dependent manner [19]. Elevated GR activities were detected in response to CD-treatment in a variety of plant species such as
Glutathione peroxidases (GPXs) are a large family of broad substrate spectrum multiple isozymes. Contrary to most of their counterparts in animal cells, plant GPXs contain cysteine instead of selenocysteine in their active site. Antioxidant GPX protecting cells from oxidative damage by reducing H2O2, organic and lipid hydroperoxides in association with the GSH pool [22]. Presence of GPXs were detected in cytosol, chloroplasts, mitochondria, peroxisome and apoplast.
Stress responses of GPXs are contradictory. Cd stress increased GPX activity in cultivars of
Glutathione S-transferases (glutathione sulfo-transferases, GSTs) are major phase II, GSH-dependent detoxication enzyme superfamily. GSTs catalyze the conjugation of glutathione (GSH) to a wide variety of endogenous and exogenous electrophilic compounds to form water soluble, non-toxic GSH conjugates [27, 28]. GSTs are divided into two distinct super-family members: the membrane-bound microsomal and cytosolic family members. Microsomal GSTs are structurally distinct from the cytosolic in that they homo- and heterotrimerize rather than dimerize to form a single active site [29]. In cytoplasm GSTs account for roughly 1% of soluble proteins in maize leaves [30]. Various plant GST izozymes were shown to possess with GSTs/GPX activity mediating lipid hydroperoxide metabolism to non-toxic alcohols [31].
Elevated GST activities were found in leaves and roots of Cd exposed pea plants [24] and in roots of
One of the detoxication mechanisms in plants to overcome heavy metal stress is the production of thiol-containing oligomer peptides from a precursor glutathione (GSH) by phytochelatin synthase (PCS, γ-glutamylcysteine dipeptidyltranspeptidase) (Figure 2).
General structure of (a) and biosynthesis (b) phytochelatins.
PC synthase-deficient mutants of
As a result of Cys residues PCs have high thiol (SH) contents and ability to strongly bind heavy metals exhibiting increased metal-binding capacity with increasing size [39]. PCs chain lengths varies with plant species and metal forms. The relative affinity of metals such as Cd, Pb, Hg, Cu to GSH and PCn oligomers increases with chain length (GSH < PC2 < PC3 < PC4) [40]. After the formation, the high molecular weight metal-phytochelatin complexes are sequestered in the vacuoles by the involvement of ABC-type (ATP-binding casette) transporters [41]. PC synthase was shown to be activated by heavy metal ions such as Cd2+, Cu2+, Ag+, Hg2+, Pb2+, Ni2+. Cd tolerance of
Cd2+ ions were found as the most effective stimulator of PCs biosynthesis and 4-6-fold higher induction of PCs were detected than with Cu2+ and Zn2+ compounds in cell cultures of Indian snakeroot (
Biosynthesis of PCs takes place in the cytosol of root cells. PCs are produced from glutathione, homoglutathione, hydroxymethyl-gluthathione or glutamylcysteinyl-glutamate by a transpeptidase, the constitutive PC synthase enzyme [45]. In
PCs enzyme activities were not only also induced Cd stress. The principal mechanism of intracellular metal detoxification by complexing and transporting metals into the vacuole was also established for stress by various heavy metals such as mercury, copper, arsenic, silver, nickel, gold, and zinc [52, 53, 54].
Stochiometry of complexes of Pb2+ formed with various PCn (n = 2–4) were examined in details. Mass spectrometry analysis of Pb– PC2 revealed four different complexes corresponding to [Pb–PC2]+, [Pb2–PC2]+, [Pb–(PC2)2]+, and [Pb2– (PC2)2]+. The coordination of Pb2+ with PC2 was postulated via the thiol groups of cysteine residue of PC2 and possibly by carboxylic groups. In case of PC3 and PC4, two complexes were detected for each metal such as Pb–PC3, Pb2–PC3, Pb–PC4, and Pb2–PC4 [55]. The metal-PCn complexes formed with Cd2+ differed from those of Pb2+. Higher metal/peptide molar ratios were estimated in Cd-PCn complexes than in Pb-PCn complexes (n = 3, 4), suggesting that phytochelatins of marine algae
Involvement of MTs has been reported in a number of physiological processes such as regulation of cell growth and proliferation, toxic metal protection and homeostasis, free radical scavenging or protection from oxidative stress, DNA damage repair [57]. For a long MTs was considered to be expressed only in mammals while in plants enzymatically formed PCs are the protective biomolecules against heavy metal toxicity. MTs is a cytosolic superfamily of cysteine-rich proteins capable to bind both physiological and xenobiotic heavy metals [58, 59]. While phytochelatins are formed enzymatically MTs are the products of mRNA translation [60, 61]. In the structure of MTs cysteine (C) residues representing about 30% of the constitutional amino acids. Primary structures of this low molecular weight protein family (Mw ranging from 5 to10 kDa) are characteristically rich in highly conserved CC, CXC (where X is a general amino acid) and CXXC motifs that render a unique ability to bind mono- or divalent metal ions, such as Cu2+, Zn2+and Cd2+ [62]. While in animal MTs no aromatic acids occur histidine (His) residues can be found in a number of plant MT sequences. The replacement a part of the Cys residues by His would be an increased selectivity for Zn2+ over Cd2+, and thus the function of the respective MT is more selective in maintaining Zn2+ homeostasis than heavy metal detoxification [63]. In addition, the thiol(ate)s in MTs can act as powerful antioxidants, and therefore MTs have definite roles in protection against oxidative stress [64].
Based on the arrangement of Cys residues four types of plant MTs exist [59]. Type 1 MTs are mainly expressed in roots, while the expression of type 2 MTs mostly occurs in shoots, type 3 MTs are induced in leaves and during fruit ripening, and type 4 MTs are abundant in the developing seeds [65]. Regarding high level of sequence diversity of plant metallothioneins, type 1-4 MTs is further subdivided to various isoforms. All four types of plant MTs and their isoforms are able to chelate heavy metals. In general, the primary structures of plant MTs in type 1, 2 and 3 have a similar cysteine topology. The two Cys-rich domains (α and β) are attached by a 30-40 amino acid long cysteine-poor linker depending on plant species. Cysteine topology of type 4 MTs different from that observed in MTs of type 1-3. In angiosperm species three Cys-rich regions linked by two Cys-poor linkers containing 15 and 40 amino acids [58, 60]. Experiments with
Studies on copper tolerance and expression MT1 and MT2 genes in several
MTs typically bind metal ions in characteristic metal– thiolate clusters that provide high thermodynamic stability coupled with kinetic lability [69]. The large diversity in the metal binding regions of plant MTs confers the ability to bind a greater range of metals than in animals possessing a greater range of function [59]. A model of cadmium binding to mammalian MTs showed that all cysteine residues participate in the coordination of 7 mol of Cd per mol of MT. Two polynuclear metal clusters formed during binding with 3 and 4 metal atoms on β- and α-domain, respectively.
In one metal cluster requires 9 cysteine SH group to bind 3 Cd in a six-membered ring while the four-metal-cluster forms a bicyclo[3.1.3] structure with the participation of 11 Cys-SH groups (Figure 3) [70].
Proposed structures of the four-metal and three-metal clusters of rat liver metallothioneins based on 113Cd NMR data [
Experimentally and predicted stochiometries of metal-plant MTs are in agreement. Type 1 plant MTs with 12 Cys residues can bind 4-5 metal ions, type 2 with 14 Cys can coordinate 5 metal ions while type 3 MTs with only 10 Cys residues exhibit the lowest capacity for metal binding (4 metal ions) [58].
The key characteristics of metal-MT complexes are the high thermodynamic but low kinetic stability. Thermodynamically, MTs are the most stable zinc sites in eukaryotes but have appropriate kinetic lability for the protein to intermolecularly exchange zinc with proteins [72]. Metal binding affinities of MTs characterized by complex stability constants are hardly available in the literature. However, pH of half-displacement values (pH (1/2)) are available for several plant MTs indicating that the more stable protein-metal complex have lower pH(1/2) value [63]. pH(1/2) values for all MTs follow the order Cu(I) < Cd(II) < Zn(II). Accordingly, MTs will bind Cu(I)
Further studies on large and complex MT gene families in higher plants may exhibit beneficial metal binding and induction properties to enhance the phytoremediation capacity of plants used for heavy metal removal in soils. To understand the function and the mechanism of action of plant MTs requires further manipulations on the expression of this protein family.
Proline (Pro) is an essential proteinogenic amino acid that fulfill several developmental functions in plants and has a fundamental role in responses to biotic and abiotic stress. In plants proline can protect cells from environmental stress factors by several protective mechanisms such as acting as osmoprotectant, functioning as chemical chaperone stabilizing proteins and antioxidant enzymes, chelating metals, scavenging reactive oxygen species (ROS), balancing the intracellular redox homeostasis (NADP+/NADPH ratio, GSH pool) and participating in cellular metabolic signaling [74, 75, 76].
Protective mechanism of proline as ROS scavanger include direct reaction with ROS. Free and polypeptide-bound proline was demonstrated to react with hydrogen peroxide (H2O2) and hydroxy radicals (OH.) producing stable free radical adducts and hydroxyproline (Figure 4). However, the most important ROS-scavenging mechanism in the stress protection is the reaction with singlet oxygen (1O2). A direct reaction between H2O2 and proline plays a minor role in scavenging of cellular H2O2 and the formation of nitroxyl radical accumulate during is very sluggish as compared to that of proline and OH.. Nevertheless, proline effectively quenches 1O2 via a charge transfer mechanism to form the ground triplet oxygen (3O2) as a ground state molecular oxygen. Due to its action as a 1O2 quencher, proline may help stabilize proteins, DNA, and membranes [77].
Routes for scavenging reactive oxygen species (ROS) by proline. Adapted from Liang et al., 2013 [
Toxic action of lead, copper, and zinc on proline, malondialdehyde (MDA), and superoxide dismutase (SOD) has been studied in the cyanobacterium
The molecular mechanism of proline protection of cells during stress may involve the effects on redox systems such as the glutathione (GSH) pool. Pro reduces heavy metal stress by detoxification of free radicals produced as a result of Cd poisoning. Pro may physically quench oxygen singlets or react directly with hydroxyl radicals. These reactions result in reduced free radical damage (lower malondialdehyde levels) and a more reducing cellular environment (higher GSH levels). The high GSH levels in turn facilitate phytochelatin synthesis and sequestration of heavy metal phytochelatin conjugates in the vacuole. This enhanced sequestration of Cd-phytochelatin complexes in the vacuole accounts for the transiently increased Cd content of P5CS (Δ1-pyrroline-5-carboxylate synthetase)-expressing cells in transgenic algae (Figure 5) [76].
Participation of proline in reducing cadmium stress by detoxification of free radicals generated by Cd toxicity. In wild type algae (
The chelation of metals is also considered as possible mechanism responsible for the protective effect of proline in cells against stress. Reversal on Cd- and Zn-induced inhibition of glucose-6-phosphate dehydrogenase and nitrate reductase enzymes by proline supported the function of proline as a metal chelator by forming proline-metal complexes [79]. Nevertheless, the stability of metal-proline complexes was found to be relatively low [80]. to effectively influence the inhibitory concentration of the metal ions in the assay mixtures. A copper–proline complex was found in the roots of copper-tolerant sea thrift (
Accumulation of free proline plants in response to abiotic stresses has been demonstrated by Delauney and Verma [81]. In
It seems that two mechanisms are responsible by which proline provides protection against heavy metal stressors. One of these, up-regulation of proline biosynthesis to accumulate proline to serve as an osmolyte, a chemical chaperone, and a direct scavenger of hydroxyl radical and singlet oxygen. Secondly, linkage of proline metabolic flux to metabolic pathways to maintain the intracellular redox homeostasis (NADP+/NADPH ratio, GSH pool).
Oxidized fatty acids, oxylipins, are an important class of signaling molecule in plants in responses to abiotic stresses [95, 96].
Oxylipins regulate growth, development, and responses to environmental stimuli of organisms [97]. Lipoxygenases, allene oxide synthase and a series of cytochromes P450 related oxygenasesare involved in oxylipin biosynthesis. Enzymatically synthesized oxylipin, the jasmonic acid (JA) and a precursor molecule 12-oxo-phytodienoic acid (OPDA) were shown to accumulate in response to pathogen infection [98]. Jasmonate-dependent tolerance to heavy metals is mediated by defensins, small cysteine-rich proteins present in plant cells [99, 100]. Oxylipins are involved in stress signal transduction, regulate stress-induced gene expression, and interact with other signaling pathways in plant cells, including signaling pathways of the plant hormones auxin, gibberellin, ethylene, and abscisic acid (ABA) [101, 102]. However, the role of oxylipins in plant adaptation and defense mechanism to abiotic stress is less studied. Protective action of oxylipins at toxic levels of heavy metals is considered to activate detoxification processes. Non-enzymatic reaction of reactive oxygen species with lipidic substances results in hydroxy fatty acids which are biologically active oxylipins and play important role in protective action of heavy metal stress [103]. Spontaneously formed oxylipins are called phytoprostanes. Pretreatment of tobacco plants with phytoprostanes results in reduction of cell death in response to copper sulfate stress [104]. In roots of tobacco seedlings Al-induced accumulation of 2-alkenals formed from fatty acid hydroperoxides was detected [105]. ROS generated during aluminum stress formed toxic aldehydes in reaction with fatty acids and caused severe root growth inhibition. Removal of 2-alkenals from tissue through overexpression of 2-alkenal reductase reduced Al phytotoxicity. Stimulation the expression of a number of stress responsive by phytoprostanes [106] makes oxylipins promising tools for improving stress tolerance of plants to heavy metals.
Heavy metal stress on plants in contaminated soils due to increased anthropogenetic activities led to an intensive research on detoxification and sequestering mechanisms of plants to understand and manipulate defense mechanisms developed in plants to tolerate stress by metal ions. The accumulation of heavy metals in plant organs results in the damage of the structural components and disruption of cell metabolic processes leading to plant growth retardation. Increased biosynthesis of various plant biomolecules to confer tolerance during toxic action of heavy metals is an intrinsic ability of plants. Induced formation of low-molecular weight amino acids, peptides or proteines as chelators such as proline (Pro), glutathione (GSH), phytochelatins (PCs) or metallothioneins (MTs) under heavy metal stress enhances metal binding and detoxification capability of plants. In addition, proline and GSH related enzymes such as GSH reductase, GSH peroxidases and glutathione S-transferases are also key components of the antioxidant defense system in the cells to scavenge reactive oxygen species (ROS). Protective action of oxidized fatty acids oxylipins at toxic levels of heavy metals is considered to activate detoxification processes as signaling molecules.
Exploring and manipulating genes induced under heavy metal stress make possible to develop transgenic plants with enhanced detoxication properties for phytoremediation technologies in polluted soils. The use of hyperaccumulator plants [107] which can accumulate heavy metals in the leaves at 100-fold higher concentration than normal plant species can be the alternative solution to clean-up polluted soils.
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\\n\\nA Corrigendum will be issued by the Academic Editor when it is determined that a mistake in a Chapter is a result of an Author’s miscalculation or oversight. A published Corrigendum will adhere to the Retraction Notice publishing guidelines outlined above.
\\n\\n4. FINAL REMARKS
\\n\\nIntechOpen wishes to emphasize that the final decision on whether a Retraction, Statement of Concern, or a Correction will be issued rests with the Academic Editor. The publisher is obliged to act upon any reports of scientific misconduct in its publications and to make a reasonable effort to facilitate any subsequent investigation of such claims.
\\n\\nIn the case of Retraction or removal of the Work, the publisher will be under no obligation to refund the APC.
\\n\\nThe general principles set out above apply to Retractions and Corrections issued in all IntechOpen publications.
\\n\\nAny suggestions or comments on this Policy are welcome and may be sent to permissions@intechopen.com.
\\n\\nPolicy last updated: 2017-09-11
\\n"}]'},components:[{type:"htmlEditorComponent",content:'IntechOpen’s Retraction and Correction Policy has been developed in accordance with the Committee on Publication Ethics (COPE) publication guidelines relating to scientific misconduct and research ethics:
\n\n1. RETRACTIONS
\n\nA Retraction of a Chapter will be issued by the Academic Editor, either following an Author’s request to do so or when there is a 3rd party report of scientific misconduct. Upon receipt of a report by a 3rd party, the Academic Editor will investigate any allegations of scientific misconduct, working in cooperation with the Author(s) and their institution(s).
\n\nA formal Retraction will be issued when there is clear and conclusive evidence of any of the following:
\n\nPublishing of a Retraction Notice will adhere to the following guidelines:
\n\n1.2. REMOVALS AND CANCELLATIONS
\n\n2. STATEMENTS OF CONCERN
\n\nA Statement of Concern detailing alleged misconduct will be issued by the Academic Editor or publisher following a 3rd party report of scientific misconduct when:
\n\nIntechOpen believes that the number of occasions on which a Statement of Concern is issued will be very few in number. In all cases when such a decision has been taken by the Academic Editor the decision will be reviewed by another editor to whom the author can make representations.
\n\n3. CORRECTIONS
\n\nA Correction will be issued by the Academic Editor when:
\n\n3.1. ERRATUM
\n\nAn Erratum will be issued by the Academic Editor when it is determined that a mistake in a Chapter originates from the production process handled by the publisher.
\n\nA published Erratum will adhere to the Retraction Notice publishing guidelines outlined above.
\n\n3.2. CORRIGENDUM
\n\nA Corrigendum will be issued by the Academic Editor when it is determined that a mistake in a Chapter is a result of an Author’s miscalculation or oversight. A published Corrigendum will adhere to the Retraction Notice publishing guidelines outlined above.
\n\n4. FINAL REMARKS
\n\nIntechOpen wishes to emphasize that the final decision on whether a Retraction, Statement of Concern, or a Correction will be issued rests with the Academic Editor. The publisher is obliged to act upon any reports of scientific misconduct in its publications and to make a reasonable effort to facilitate any subsequent investigation of such claims.
\n\nIn the case of Retraction or removal of the Work, the publisher will be under no obligation to refund the APC.
\n\nThe general principles set out above apply to Retractions and Corrections issued in all IntechOpen publications.
\n\nAny suggestions or comments on this Policy are welcome and may be sent to permissions@intechopen.com.
\n\nPolicy last updated: 2017-09-11
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He obtained a Master’s degree in Public Health and PhD in Public Health and Epidemiology. He has a background in Clinical Medicine and has taken courses at higher diploma levels in public health from University of Transkei, Republic of South Africa, and African Medical and Research Foundation (AMREF) in Nairobi, Kenya. Dr. Kasenga worked in different places in and outside Malawi, and has held various positions, such as Licensed Medical Officer, HIV/AIDS Programme Officer, HIV/AIDS resource person in the International Department of Diakonhjemet College, Oslo, Norway. He also managed an Integrated HIV/AIDS Prevention programme for over 5 years. He is currently working as a Director for the Health Ministries Department of Malawi Union of the Seventh Day Adventist Church. Dr. Kasenga has published over 5 articles on HIV/AIDS issues focusing on Prevention of Mother to Child Transmission of HIV (PMTCT), including a book chapter on HIV testing counseling (currently in press). 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Buchholz",profilePictureURL:"https://mts.intechopen.com/storage/users/89438/images/6463_n.jpg",institutionString:null,institution:{name:"Loma Linda University",institutionURL:null,country:{name:"United States of America"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null}]},subseriesFiltersForPublishedBooks:[{group:"subseries",caption:"Plant Physiology",value:13,count:1},{group:"subseries",caption:"Human Physiology",value:12,count:2},{group:"subseries",caption:"Cell Physiology",value:11,count:8}],publicationYearFilters:[{group:"publicationYear",caption:"2022",value:2022,count:1},{group:"publicationYear",caption:"2020",value:2020,count:4},{group:"publicationYear",caption:"2019",value:2019,count:5},{group:"publicationYear",caption:"2018",value:2018,count:1}],authors:{paginationCount:302,paginationItems:[{id:"198499",title:"Dr.",name:"Daniel",middleName:null,surname:"Glossman-Mitnik",slug:"daniel-glossman-mitnik",fullName:"Daniel Glossman-Mitnik",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/198499/images/system/198499.jpeg",biography:"Dr. Daniel Glossman-Mitnik is currently a Titular Researcher at the Centro de Investigación en Materiales Avanzados (CIMAV), Chihuahua, Mexico, as well as a National Researcher of Level III at the Consejo Nacional de Ciencia y Tecnología, Mexico. His research interest focuses on computational chemistry and molecular modeling of diverse systems of pharmacological, food, and alternative energy interests by resorting to DFT and Conceptual DFT. He has authored a coauthored more than 255 peer-reviewed papers, 32 book chapters, and 2 edited books. He has delivered speeches at many international and domestic conferences. He serves as a reviewer for more than eighty international journals, books, and research proposals as well as an editor for special issues of renowned scientific journals.",institutionString:"Centro de Investigación en Materiales Avanzados",institution:{name:"Centro de Investigación en Materiales Avanzados",country:{name:"Mexico"}}},{id:"76477",title:"Prof.",name:"Mirza",middleName:null,surname:"Hasanuzzaman",slug:"mirza-hasanuzzaman",fullName:"Mirza Hasanuzzaman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/76477/images/system/76477.png",biography:"Dr. Mirza Hasanuzzaman is a Professor of Agronomy at Sher-e-Bangla Agricultural University, Bangladesh. He received his Ph.D. in Plant Stress Physiology and Antioxidant Metabolism from Ehime University, Japan, with a scholarship from the Japanese Government (MEXT). Later, he completed his postdoctoral research at the Center of Molecular Biosciences, University of the Ryukyus, Japan, as a recipient of the Japan Society for the Promotion of Science (JSPS) postdoctoral fellowship. He was also the recipient of the Australian Government Endeavour Research Fellowship for postdoctoral research as an adjunct senior researcher at the University of Tasmania, Australia. Dr. Hasanuzzaman’s current work is focused on the physiological and molecular mechanisms of environmental stress tolerance. Dr. Hasanuzzaman has published more than 150 articles in peer-reviewed journals. He has edited ten books and written more than forty book chapters on important aspects of plant physiology, plant stress tolerance, and crop production. According to Scopus, Dr. Hasanuzzaman’s publications have received more than 10,500 citations with an h-index of 53. He has been named a Highly Cited Researcher by Clarivate. He is an editor and reviewer for more than fifty peer-reviewed international journals and was a recipient of the “Publons Peer Review Award” in 2017, 2018, and 2019. He has been honored by different authorities for his outstanding performance in various fields like research and education, and he has received the World Academy of Science Young Scientist Award (2014) and the University Grants Commission (UGC) Award 2018. He is a fellow of the Bangladesh Academy of Sciences (BAS) and the Royal Society of Biology.",institutionString:"Sher-e-Bangla Agricultural University",institution:{name:"Sher-e-Bangla Agricultural University",country:{name:"Bangladesh"}}},{id:"187859",title:"Prof.",name:"Kusal",middleName:"K.",surname:"Das",slug:"kusal-das",fullName:"Kusal Das",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSBDeQAO/Profile_Picture_1623411145568",biography:"Kusal K. Das is a Distinguished Chair Professor of Physiology, Shri B. M. Patil Medical College and Director, Centre for Advanced Medical Research (CAMR), BLDE (Deemed to be University), Vijayapur, Karnataka, India. Dr. Das did his M.S. and Ph.D. in Human Physiology from the University of Calcutta, Kolkata. His area of research is focused on understanding of molecular mechanisms of heavy metal activated low oxygen sensing pathways in vascular pathophysiology. He has invented a new method of estimation of serum vitamin E. His expertise in critical experimental protocols on vascular functions in experimental animals was well documented by his quality of publications. He was a Visiting Professor of Medicine at University of Leeds, United Kingdom (2014-2016) and Tulane University, New Orleans, USA (2017). For his immense contribution in medical research Ministry of Science and Technology, Government of India conferred him 'G.P. Chatterjee Memorial Research Prize-2019” and he is also the recipient of 'Dr.Raja Ramanna State Scientist Award 2015” by Government of Karnataka. He is a Fellow of the Royal Society of Biology (FRSB), London and Honorary Fellow of Karnataka Science and Technology Academy, Department of Science and Technology, Government of Karnataka.",institutionString:"BLDE (Deemed to be University), India",institution:null},{id:"243660",title:"Dr.",name:"Mallanagouda Shivanagouda",middleName:null,surname:"Biradar",slug:"mallanagouda-shivanagouda-biradar",fullName:"Mallanagouda Shivanagouda Biradar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243660/images/system/243660.jpeg",biography:"M. S. Biradar is Vice Chancellor and Professor of Medicine of\nBLDE (Deemed to be University), Vijayapura, Karnataka, India.\nHe obtained his MD with a gold medal in General Medicine and\nhas devoted himself to medical teaching, research, and administrations. He has also immensely contributed to medical research\non vascular medicine, which is reflected by his numerous publications including books and book chapters. Professor Biradar was\nalso Visiting Professor at Tulane University School of Medicine, New Orleans, USA.",institutionString:"BLDE (Deemed to be University)",institution:{name:"BLDE University",country:{name:"India"}}},{id:"289796",title:"Dr.",name:"Swastika",middleName:null,surname:"Das",slug:"swastika-das",fullName:"Swastika Das",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/289796/images/system/289796.jpeg",biography:"Swastika N. Das is Professor of Chemistry at the V. P. Dr. P. G.\nHalakatti College of Engineering and Technology, BLDE (Deemed\nto be University), Vijayapura, Karnataka, India. She obtained an\nMSc, MPhil, and PhD in Chemistry from Sambalpur University,\nOdisha, India. Her areas of research interest are medicinal chemistry, chemical kinetics, and free radical chemistry. She is a member\nof the investigators who invented a new modified method of estimation of serum vitamin E. She has authored numerous publications including book\nchapters and is a mentor of doctoral curriculum at her university.",institutionString:"BLDEA’s V.P.Dr.P.G.Halakatti College of Engineering & Technology",institution:{name:"BLDE University",country:{name:"India"}}},{id:"248459",title:"Dr.",name:"Akikazu",middleName:null,surname:"Takada",slug:"akikazu-takada",fullName:"Akikazu Takada",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248459/images/system/248459.png",biography:"Akikazu Takada was born in Japan, 1935. After graduation from\nKeio University School of Medicine and finishing his post-graduate studies, he worked at Roswell Park Memorial Institute NY,\nUSA. He then took a professorship at Hamamatsu University\nSchool of Medicine. In thrombosis studies, he found the SK\npotentiator that enhances plasminogen activation by streptokinase. He is very much interested in simultaneous measurements\nof fatty acids, amino acids, and tryptophan degradation products. By using fatty\nacid analyses, he indicated that plasma levels of trans-fatty acids of old men were\nfar higher in the US than Japanese men. . He also showed that eicosapentaenoic acid\n(EPA) and docosahexaenoic acid (DHA) levels are higher, and arachidonic acid\nlevels are lower in Japanese than US people. By using simultaneous LC/MS analyses\nof plasma levels of tryptophan metabolites, he recently found that plasma levels of\nserotonin, kynurenine, or 5-HIAA were higher in patients of mono- and bipolar\ndepression, which are significantly different from observations reported before. In\nview of recent reports that plasma tryptophan metabolites are mainly produced by\nmicrobiota. He is now working on the relationships between microbiota and depression or autism.",institutionString:"Hamamatsu University School of Medicine",institution:{name:"Hamamatsu University School of Medicine",country:{name:"Japan"}}},{id:"137240",title:"Prof.",name:"Mohammed",middleName:null,surname:"Khalid",slug:"mohammed-khalid",fullName:"Mohammed Khalid",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/137240/images/system/137240.png",biography:"Mohammed Khalid received his B.S. degree in chemistry in 2000 and Ph.D. degree in physical chemistry in 2007 from the University of Khartoum, Sudan. He moved to School of Chemistry, Faculty of Science, University of Sydney, Australia in 2009 and joined Dr. Ron Clarke as a postdoctoral fellow where he worked on the interaction of ATP with the phosphoenzyme of the Na+/K+-ATPase and dual mechanisms of allosteric acceleration of the Na+/K+-ATPase by ATP; then he went back to Department of Chemistry, University of Khartoum as an assistant professor, and in 2014 he was promoted as an associate professor. In 2011, he joined the staff of Department of Chemistry at Taif University, Saudi Arabia, where he is currently an assistant professor. His research interests include the following: P-Type ATPase enzyme kinetics and mechanisms, kinetics and mechanisms of redox reactions, autocatalytic reactions, computational enzyme kinetics, allosteric acceleration of P-type ATPases by ATP, exploring of allosteric sites of ATPases, and interaction of ATP with ATPases located in cell membranes.",institutionString:"Taif University",institution:{name:"Taif University",country:{name:"Saudi Arabia"}}},{id:"63810",title:"Prof.",name:"Jorge",middleName:null,surname:"Morales-Montor",slug:"jorge-morales-montor",fullName:"Jorge Morales-Montor",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/63810/images/system/63810.png",biography:"Dr. Jorge Morales-Montor was recognized with the Lola and Igo Flisser PUIS Award for best graduate thesis at the national level in the field of parasitology. He received a fellowship from the Fogarty Foundation to perform postdoctoral research stay at the University of Georgia. He has 153 journal articles to his credit. He has also edited several books and published more than fifty-five book chapters. He is a member of the Mexican Academy of Sciences, Latin American Academy of Sciences, and the National Academy of Medicine. He has received more than thirty-five awards and has supervised numerous bachelor’s, master’s, and Ph.D. students. Dr. Morales-Montor is the past president of the Mexican Society of Parasitology.",institutionString:"National Autonomous University of Mexico",institution:{name:"National Autonomous University of Mexico",country:{name:"Mexico"}}},{id:"217215",title:"Dr.",name:"Palash",middleName:null,surname:"Mandal",slug:"palash-mandal",fullName:"Palash Mandal",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/217215/images/system/217215.jpeg",biography:null,institutionString:"Charusat University",institution:null},{id:"49739",title:"Dr.",name:"Leszek",middleName:null,surname:"Szablewski",slug:"leszek-szablewski",fullName:"Leszek Szablewski",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49739/images/system/49739.jpg",biography:"Leszek Szablewski is a professor of medical sciences. He received his M.S. in the Faculty of Biology from the University of Warsaw and his PhD degree from the Institute of Experimental Biology Polish Academy of Sciences. He habilitated in the Medical University of Warsaw, and he obtained his degree of Professor from the President of Poland. Professor Szablewski is the Head of Chair and Department of General Biology and Parasitology, Medical University of Warsaw. Professor Szablewski has published over 80 peer-reviewed papers in journals such as Journal of Alzheimer’s Disease, Biochim. Biophys. Acta Reviews of Cancer, Biol. Chem., J. Biomed. Sci., and Diabetes/Metabol. Res. Rev, Endocrine. He is the author of two books and four book chapters. He has edited four books, written 15 scripts for students, is the ad hoc reviewer of over 30 peer-reviewed journals, and editorial member of peer-reviewed journals. Prof. Szablewski’s research focuses on cell physiology, genetics, and pathophysiology. He works on the damage caused by lack of glucose homeostasis and changes in the expression and/or function of glucose transporters due to various diseases. He has given lectures, seminars, and exercises for students at the Medical University.",institutionString:"Medical University of Warsaw",institution:{name:"Medical University of Warsaw",country:{name:"Poland"}}},{id:"173123",title:"Dr.",name:"Maitham",middleName:null,surname:"Khajah",slug:"maitham-khajah",fullName:"Maitham Khajah",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/173123/images/system/173123.jpeg",biography:"Dr. Maitham A. Khajah received his degree in Pharmacy from Faculty of Pharmacy, Kuwait University, in 2003 and obtained his PhD degree in December 2009 from the University of Calgary, Canada (Gastrointestinal Science and Immunology). Since January 2010 he has been assistant professor in Kuwait University, Faculty of Pharmacy, Department of Pharmacology and Therapeutics. His research interest are molecular targets for the treatment of inflammatory bowel disease (IBD) and the mechanisms responsible for immune cell chemotaxis. He cosupervised many students for the MSc Molecular Biology Program, College of Graduate Studies, Kuwait University. Ever since joining Kuwait University in 2010, he got various grants as PI and Co-I. He was awarded the Best Young Researcher Award by Kuwait University, Research Sector, for the Year 2013–2014. He was a member in the organizing committee for three conferences organized by Kuwait University, Faculty of Pharmacy, as cochair and a member in the scientific committee (the 3rd, 4th, and 5th Kuwait International Pharmacy Conference).",institutionString:"Kuwait University",institution:{name:"Kuwait University",country:{name:"Kuwait"}}},{id:"195136",title:"Dr.",name:"Aya",middleName:null,surname:"Adel",slug:"aya-adel",fullName:"Aya Adel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/195136/images/system/195136.jpg",biography:"Dr. Adel works as an Assistant Lecturer in the unit of Phoniatrics, Department of Otolaryngology, Ain Shams University in Cairo, Egypt. Dr. Adel is especially interested in joint attention and its impairment in autism spectrum disorder",institutionString:"Ain Shams University",institution:{name:"Ain Shams University",country:{name:"Egypt"}}},{id:"94911",title:"Dr.",name:"Boulenouar",middleName:null,surname:"Mesraoua",slug:"boulenouar-mesraoua",fullName:"Boulenouar Mesraoua",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94911/images/system/94911.png",biography:"Dr Boulenouar Mesraoua is the Associate Professor of Clinical Neurology at Weill Cornell Medical College-Qatar and a Consultant Neurologist at Hamad Medical Corporation at the Neuroscience Department; He graduated as a Medical Doctor from the University of Oran, Algeria; he then moved to Belgium, the City of Liege, for a Residency in Internal Medicine and Neurology at Liege University; after getting the Belgian Board of Neurology (with high marks), he went to the National Hospital for Nervous Diseases, Queen Square, London, United Kingdom for a fellowship in Clinical Neurophysiology, under Pr Willison ; Dr Mesraoua had also further training in Epilepsy and Continuous EEG Monitoring for two years (from 2001-2003) in the Neurophysiology department of Zurich University, Switzerland, under late Pr Hans Gregor Wieser ,an internationally known epileptologist expert. \n\nDr B. Mesraoua is the Director of the Neurology Fellowship Program at the Neurology Section and an active member of the newly created Comprehensive Epilepsy Program at Hamad General Hospital, Doha, Qatar; he is also Assistant Director of the Residency Program at the Qatar Medical School. \nDr B. Mesraoua's main interests are Epilepsy, Multiple Sclerosis, and Clinical Neurology; He is the Chairman and the Organizer of the well known Qatar Epilepsy Symposium, he is running yearly for the past 14 years and which is considered a landmark in the Gulf region; He has also started last year , together with other epileptologists from Qatar, the region and elsewhere, a yearly International Epilepsy School Course, which was attended by many neurologists from the Area.\n\nInternationally, Dr Mesraoua is an active and elected member of the Commission on Eastern Mediterranean Region (EMR ) , a regional branch of the International League Against Epilepsy (ILAE), where he represents the Middle East and North Africa(MENA ) and where he holds the position of chief of the Epilepsy Epidemiology Section; Dr Mesraoua is a member of the American Academy of Neurology, the Europeen Academy of Neurology and the American Epilepsy Society.\n\nDr Mesraoua's main objectives are to encourage frequent gathering of the epileptologists/neurologists from the MENA region and the rest of the world, promote Epilepsy Teaching in the MENA Region, and encourage multicenter studies involving neurologists and epileptologists in the MENA region, particularly epilepsy epidemiological studies. \n\nDr. Mesraoua is the recipient of two research Grants, as the Lead Principal Investigator (750.000 USD and 250.000 USD) from the Qatar National Research Fund (QNRF) and the Hamad Hospital Internal Research Grant (IRGC), on the following topics : “Continuous EEG Monitoring in the ICU “ and on “Alpha-lactoalbumin , proof of concept in the treatment of epilepsy” .Dr Mesraoua is a reviewer for the journal \"seizures\" (Europeen Epilepsy Journal ) as well as dove journals ; Dr Mesraoua is the author and co-author of many peer reviewed publications and four book chapters in the field of Epilepsy and Clinical Neurology",institutionString:"Weill Cornell Medical College in Qatar",institution:{name:"Weill Cornell Medical College in Qatar",country:{name:"Qatar"}}},{id:"282429",title:"Prof.",name:"Covanis",middleName:null,surname:"Athanasios",slug:"covanis-athanasios",fullName:"Covanis Athanasios",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/282429/images/system/282429.jpg",biography:null,institutionString:"Neurology-Neurophysiology Department of the Children Hospital Agia Sophia",institution:null},{id:"190980",title:"Prof.",name:"Marwa",middleName:null,surname:"Mahmoud Saleh",slug:"marwa-mahmoud-saleh",fullName:"Marwa Mahmoud Saleh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/190980/images/system/190980.jpg",biography:"Professor Marwa Mahmoud Saleh is a doctor of medicine and currently works in the unit of Phoniatrics, Department of Otolaryngology, Ain Shams University in Cairo, Egypt. She got her doctoral degree in 1991 and her doctoral thesis was accomplished in the University of Iowa, United States. Her publications covered a multitude of topics as videokymography, cochlear implants, stuttering, and dysphagia. She has lectured Egyptian phonology for many years. Her recent research interest is joint attention in autism.",institutionString:"Ain Shams University",institution:{name:"Ain Shams University",country:{name:"Egypt"}}},{id:"259190",title:"Dr.",name:"Syed Ali Raza",middleName:null,surname:"Naqvi",slug:"syed-ali-raza-naqvi",fullName:"Syed Ali Raza Naqvi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259190/images/system/259190.png",biography:"Dr. Naqvi is a radioanalytical chemist and is working as an associate professor of analytical chemistry in the Department of Chemistry, Government College University, Faisalabad, Pakistan. Advance separation techniques, nuclear analytical techniques and radiopharmaceutical analysis are the main courses that he is teaching to graduate and post-graduate students. In the research area, he is focusing on the development of organic- and biomolecule-based radiopharmaceuticals for diagnosis and therapy of infectious and cancerous diseases. Under the supervision of Dr. Naqvi, three students have completed their Ph.D. degrees and 41 students have completed their MS degrees. He has completed three research projects and is currently working on 2 projects entitled “Radiolabeling of fluoroquinolone derivatives for the diagnosis of deep-seated bacterial infections” and “Radiolabeled minigastrin peptides for diagnosis and therapy of NETs”. He has published about 100 research articles in international reputed journals and 7 book chapters. Pakistan Institute of Nuclear Science & Technology (PINSTECH) Islamabad, Punjab Institute of Nuclear Medicine (PINM), Faisalabad and Institute of Nuclear Medicine and Radiology (INOR) Abbottabad are the main collaborating institutes.",institutionString:"Government College University",institution:{name:"Government College University, Faisalabad",country:{name:"Pakistan"}}},{id:"58390",title:"Dr.",name:"Gyula",middleName:null,surname:"Mozsik",slug:"gyula-mozsik",fullName:"Gyula Mozsik",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/58390/images/system/58390.png",biography:"Gyula Mózsik MD, Ph.D., ScD (med), is an emeritus professor of Medicine at the First Department of Medicine, Univesity of Pécs, Hungary. He was head of this department from 1993 to 2003. His specializations are medicine, gastroenterology, clinical pharmacology, clinical nutrition, and dietetics. His research fields are biochemical pharmacological examinations in the human gastrointestinal (GI) mucosa, mechanisms of retinoids, drugs, capsaicin-sensitive afferent nerves, and innovative pharmacological, pharmaceutical, and nutritional (dietary) research in humans. He has published about 360 peer-reviewed papers, 197 book chapters, 692 abstracts, 19 monographs, and has edited 37 books. He has given about 1120 regular and review lectures. He has organized thirty-eight national and international congresses and symposia. He is the founder of the International Conference on Ulcer Research (ICUR); International Union of Pharmacology, Gastrointestinal Section (IUPHAR-GI); Brain-Gut Society symposiums, and gastrointestinal cytoprotective symposiums. He received the Andre Robert Award from IUPHAR-GI in 2014. Fifteen of his students have been appointed as full professors in Egypt, Cuba, and Hungary.",institutionString:"University of Pécs",institution:{name:"University of Pecs",country:{name:"Hungary"}}},{id:"277367",title:"M.Sc.",name:"Daniel",middleName:"Martin",surname:"Márquez López",slug:"daniel-marquez-lopez",fullName:"Daniel Márquez López",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/277367/images/7909_n.jpg",biography:"Msc Daniel Martin Márquez López has a bachelor degree in Industrial Chemical Engineering, a Master of science degree in the same área and he is a PhD candidate for the Instituto Politécnico Nacional. His Works are realted to the Green chemistry field, biolubricants, biodiesel, transesterification reactions for biodiesel production and the manipulation of oils for therapeutic purposes.",institutionString:null,institution:{name:"Instituto Politécnico Nacional",country:{name:"Mexico"}}},{id:"196544",title:"Prof.",name:"Angel",middleName:null,surname:"Catala",slug:"angel-catala",fullName:"Angel Catala",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/196544/images/system/196544.jpg",biography:"Angel Catalá studied chemistry at Universidad Nacional de La Plata, Argentina, where he received a Ph.D. in Chemistry (Biological Branch) in 1965. From 1964 to 1974, he worked as an Assistant in Biochemistry at the School of Medicine at the same university. From 1974 to 1976, he was a fellow of the National Institutes of Health (NIH) at the University of Connecticut, Health Center, USA. From 1985 to 2004, he served as a Full Professor of Biochemistry at the Universidad Nacional de La Plata. He is a member of the National Research Council (CONICET), Argentina, and the Argentine Society for Biochemistry and Molecular Biology (SAIB). His laboratory has been interested for many years in the lipid peroxidation of biological membranes from various tissues and different species. Dr. Catalá has directed twelve doctoral theses, published more than 100 papers in peer-reviewed journals, several chapters in books, and edited twelve books. He received awards at the 40th International Conference Biochemistry of Lipids 1999 in Dijon, France. He is the winner of the Bimbo Pan-American Nutrition, Food Science and Technology Award 2006 and 2012, South America, Human Nutrition, Professional Category. In 2006, he won the Bernardo Houssay award in pharmacology, in recognition of his meritorious works of research. Dr. Catalá belongs to the editorial board of several journals including Journal of Lipids; International Review of Biophysical Chemistry; Frontiers in Membrane Physiology and Biophysics; World Journal of Experimental Medicine and Biochemistry Research International; World Journal of Biological Chemistry, Diabetes, and the Pancreas; International Journal of Chronic Diseases & Therapy; and International Journal of Nutrition. He is the co-editor of The Open Biology Journal and associate editor for Oxidative Medicine and Cellular Longevity.",institutionString:"Universidad Nacional de La Plata",institution:{name:"National University of La Plata",country:{name:"Argentina"}}},{id:"186585",title:"Dr.",name:"Francisco Javier",middleName:null,surname:"Martin-Romero",slug:"francisco-javier-martin-romero",fullName:"Francisco Javier Martin-Romero",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSB3HQAW/Profile_Picture_1631258137641",biography:"Francisco Javier Martín-Romero (Javier) is a Professor of Biochemistry and Molecular Biology at the University of Extremadura, Spain. He is also a group leader at the Biomarkers Institute of Molecular Pathology. Javier received his Ph.D. in 1998 in Biochemistry and Biophysics. At the National Cancer Institute (National Institute of Health, Bethesda, MD) he worked as a research associate on the molecular biology of selenium and its role in health and disease. After postdoctoral collaborations with Carlos Gutierrez-Merino (University of Extremadura, Spain) and Dario Alessi (University of Dundee, UK), he established his own laboratory in 2008. The interest of Javier's lab is the study of cell signaling with a special focus on Ca2+ signaling, and how Ca2+ transport modulates the cytoskeleton, migration, differentiation, cell death, etc. He is especially interested in the study of Ca2+ channels, and the role of STIM1 in the initiation of pathological events.",institutionString:null,institution:{name:"University of Extremadura",country:{name:"Spain"}}},{id:"217323",title:"Prof.",name:"Guang-Jer",middleName:null,surname:"Wu",slug:"guang-jer-wu",fullName:"Guang-Jer Wu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/217323/images/8027_n.jpg",biography:null,institutionString:null,institution:null},{id:"148546",title:"Dr.",name:"Norma Francenia",middleName:null,surname:"Santos-Sánchez",slug:"norma-francenia-santos-sanchez",fullName:"Norma Francenia Santos-Sánchez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/148546/images/4640_n.jpg",biography:null,institutionString:null,institution:null},{id:"272889",title:"Dr.",name:"Narendra",middleName:null,surname:"Maddu",slug:"narendra-maddu",fullName:"Narendra Maddu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/272889/images/10758_n.jpg",biography:null,institutionString:null,institution:null},{id:"242491",title:"Prof.",name:"Angelica",middleName:null,surname:"Rueda",slug:"angelica-rueda",fullName:"Angelica Rueda",position:"Investigador Cinvestav 3B",profilePictureURL:"https://mts.intechopen.com/storage/users/242491/images/6765_n.jpg",biography:null,institutionString:null,institution:null},{id:"88631",title:"Dr.",name:"Ivan",middleName:null,surname:"Petyaev",slug:"ivan-petyaev",fullName:"Ivan Petyaev",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Lycotec (United Kingdom)",country:{name:"United Kingdom"}}},{id:"423869",title:"Ms.",name:"Smita",middleName:null,surname:"Rai",slug:"smita-rai",fullName:"Smita Rai",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Integral University",country:{name:"India"}}},{id:"424024",title:"Prof.",name:"Swati",middleName:null,surname:"Sharma",slug:"swati-sharma",fullName:"Swati Sharma",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Integral University",country:{name:"India"}}},{id:"439112",title:"MSc.",name:"Touseef",middleName:null,surname:"Fatima",slug:"touseef-fatima",fullName:"Touseef Fatima",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Integral University",country:{name:"India"}}},{id:"424836",title:"Dr.",name:"Orsolya",middleName:null,surname:"Borsai",slug:"orsolya-borsai",fullName:"Orsolya Borsai",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Agricultural Sciences and Veterinary Medicine of Cluj-Napoca",country:{name:"Romania"}}},{id:"422262",title:"Ph.D.",name:"Paola Andrea",middleName:null,surname:"Palmeros-Suárez",slug:"paola-andrea-palmeros-suarez",fullName:"Paola Andrea Palmeros-Suárez",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Guadalajara",country:{name:"Mexico"}}}]}},subseries:{item:{id:"95",type:"subseries",title:"Urban Planning and Environmental Management",keywords:"Circular economy, Contingency planning and response to disasters, Ecosystem services, Integrated urban water management, Nature-based solutions, Sustainable urban development, Urban green spaces",scope:"