Multimodal analgesia comprises a combination of the following modalities.
\r\n\tThis book chapter’s main theme will be focused on transmission dynamics, pathogenesis, mechanisms of host interaction and response, epigenetics and markers, molecular diagnosis, RNA interacting proteins, RNA binding proteins, advanced development of tools for diagnosis, possible development of concepts for vaccines and anti drugs for RNA viruses, immunological mechanisms, treatment, prevention and control.
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Albert Einstein [1]
Pain is described as an unpleasant sensory and emotional sensation associated with actual or potential tissue damage [2]. Pain is a normal physiological response to injury that protects an injured area at the time of healing. The experience of pain is the consequence of neuro-inflammatory activity and its interaction with complex peripheral and central nervous information-processing networks. It is not a simple hardwired impulse to sense message. The complex sequence of electrochemical events that take place from the site of injury to perception of pain is known as nociception. External noxious energy from the site of injury is converted into electrophysiological activity (transduction). This coded information is relayed via multiple parallel ascending pathways through the spinal cord to the brainstem, thalamus and sensory cortex (transmission). Incoming nociceptive traffic can be modified at any point in this transmission pathway by descending inhibitory pathways (modulation) [3]. The periaqueductal grey region, within the midbrain, and the periventricular grey matter connect anatomically with the rostroventral medulla and send descending excitatory projections to the dorsal horn of the spinal cord. Finally, connections between the thalamus and other higher cortical centres integrate the autonomic, affective and emotional responses to give a cumulative perception of pain [4]. It is important to note that pain pathways show remarkable neuroplasticity, changing phenotype in response to sustained inputs [5].
The paediatric experience of pain is influenced by many factors including the degree of tissue damage, age, sex, pharmacogenetic profile, previous pain experiences, cognitive factors, emotional issues, behavioural aspects, family background, environment, peer groups and culture. Due to the diverse interplay of these factors, there is substantial inter-individual variability in pain perception for different child/youths who have undergone the same surgical insult. In addition inter-individual variability in response to medications due to pharmacogenetic, sex, cultural, cognitive and emotional factors means that the analgesic response to doses of analgesia medication is also not predictable. Hence, the nature of pain as a sensation and its overall significance to a child/youth is unique. The resulting uncertainty in an individual child’s pain perception and response to medications dictate that pain therapy is targeted according to ongoing individual assessment and response. Safe clinical practice requires appropriate understanding of pain pathophysiology, different pain models, pain assessment in different aged children and the age-related changes in the pharmacokinetics and pharmacodynamics of analgesics in infants and children. In an effort to comprehend why IVLT is effective, it is essential to understand some the mechanisms integral to pain physiology and pathophysiology.
Nociceptors are the free nerve endings of primary afferent pain nerve fibres responsible for the detection of noxious (unpleasant) stimuli, transforming the stimuli into electrical signals that are conducted to the central nervous system. Nocioceptors are distributed throughout the body and can be stimulated by mechanical, thermal or chemical stimuli.
Tissue injury induces an inflammatory reaction with an increase in acute phase proteins and the release of vasoactive mediators from mast cells and platelets. This inflammatory reaction includes activation of the kinin, complement and cytokine systems with release of inflammatory markers such as endothelin, prostaglandin E2, leukotrienes, substance P, bradykinin, cytokines, serotonin and adrenaline. These inflammatory markers induce peripheral nocioceptor sensitization and increased neuronal excitability [6–8]. These changes are partly caused by a change in levels of growth factors such as nerve growth factor, brain-derived neurotrophic factor, neuotrophin-3 and glial-cell derived neurotrophic factor [5].
Activation of nocioceptors creates energy that is converted into electrophysiological activity and transduced. Action potentials are created by activity of voltage-gated sodium and potassium channels which then propagate through axons to synapse in the dorsal horn [9]. The spinal-dorsal horn receives this nocioceptive information principally from primary afferent A-delta and C fibres. A-delta fibres are medium diameter myelinated axons that transmit acute afferent, localized sharp pain sensation. C fibres are small diameter un-myelinated afferents and convey delayed poorly localized pain. In the dorsal horn depolarization opens voltage-gated calcium channels (VGCC) which release substance P and glutamate that activate second-order neurons.
Following injury, the inflammatory mediators released also activate G-protein-coupled receptors expressed on sensory neurons. These are of fundamental importance for intra- and inter-cellular communication pathways [10] and play an important role in pain modulation and inflammation [11, 12]. It is relevant to note that cell membranes of injured peripheral nerves can exhibit an increased density in sodium channels and produce ectopic impulse generation and persistent spontaneous discharge in these nerves, their dorsal root ganglia, as well as neighbouring un-injured neurons [13–20]. As these spontaneous discharges have been shown to develop in both myelinated and un-myelinated nerve fibres, it is evident that ectopic activity can arise in both nociceptors and low-threshold mechanoreceptors [21]. Voltage-gated sodium channels (VGSC) with distinct gating and pharmacological properties have been reported to be upregulated in adult neurons by injury or disease [22]. An increased expression of sodium channels in dorsal root ganglia and around the injury site of injured axons contributes to spontaneous firing of nerve fibres after injury [23]. Changes in expression of sodium channels also occur in chronic neuropathic and inflammatory pain states [20, 24–28]. Changes in the properties and expression of voltage-gated calcium channels are also observed in neuropathic pain [29].
The non-selective cation channels, which make up the transient receptor potential (TRP) family of ion channels, are also key components in nocioception [30–32] and neurogenic inflammation [33, 34]. The transient receptor potential vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1) channels are members of this TRP family. TRPV1 and TRPA1 are expressed on some sensory nerves and dorsal root ganglia [35]. They inter-link considerably with each other in terms of function, except, only TRPV1 is activated by vanilloids, like capsaicin (the piquant component of chili peppers). About 97% of TRPA1-expressing sensory neurons express TRPV1, while 30% of TRPV1-expressing neurons express TRPA1 [36]. TRPA1 is a molecular sensor of potentially toxic chemicals [37, 38] and is also activated by low temperatures [38, 39], mechanical stimuli [40, 41], and elevation of intra-cellular Ca2+ [42]. TRPA1 is, therefore, involved in the generation of pain signals associated with exposure to noxious chemicals, cold and mechanical stimuli [31]. In animal models of inflammatory and neuropathic pain, TRPA1 is up-regulated in sensory neurons [43, 44] and TRPA1 antagonists have been found to exhibit analgesic properties [45–47].
The terminals of C and A-delta fibres are concentrated in the superficial dorsal horn, C and Ad fibres terminate in lamina I (marginal zone) and lamina II (substantia gelatinosa) with some Ad fibres also terminating in lamina V. These fibres activate second-order neurons as well as modulatory inter-neurons (located in laminae V and VI). Primary afferent terminals release a number of excitatory neurotransmitters including glutamate and substance P.
Primary afferent nociceptive inputs synapse in the dorsal horn utilizing alpha-amino-3-hydroxy-5-methyl-4-iso-xazolepropionate (AMPA), neurokinin-1, and calcitonin gene-related peptide. Glutamate has a fundamental role in the activation of both AMPA and N-methyl-d-aspartate (NMDA) receptors in the dorsal horn, which generate excitatory post-synaptic potentials. Substance P belongs to the neurokinin group of small peptides, its effects are mediated by its binding to the NK1 receptor. The substance P-NK1 (SP-NK1) receptor system is present in only a minority of neurons (5–7%) and only in certain areas of the central nervous system. Release of substance P is induced by injurious stimuli, and the extent of its release is proportional to the strength and frequency of stimulation.
Glycine also serves an important role in central neurotransmission. It is an inhibitory neurotransmitter, and a co-agonist with glutamate at the NMDA receptor. These actions depend on extracellular glycine levels, which are regulated by glycine transporters. Ablation or silencing of spinal glycinergic neurons induces hyperalgesia and spontaneous pain behaviours, while their activation evokes analgesia against acute and chronic pain in rodents [48]. During high neuronal activity, glycine released from inhibitory inter-neurons escapes from the synaptic cleft, reaches nearby NMDA receptors and stimulates the NMDA receptor.
It is important to realize that different pain states (i.e. neuropathic/cancer/inflammatory) do create a unique but different set of neurochemical changes within sensory neurons, dorsal root ganglia and the spinal cord [5, 49].
Information from second-order neurons is relayed via the spinal cord to the brainstem and thalamus. Connections between the thalamus and higher cortical centres integrate the affective and autonomic responses to pain perception. In addition, descending axons from the brainstem synapse and release serotonin, noradrenaline and enkephalins in dorsal horn to also modify nociceptive transmission.
Primary afferent A-beta fibres are large-diameter myelinated nerves, which transmit mechanical information such as light touch. A-beta fibres do not usually activate nociceptive neurons and therefore do not transmit pain. The terminals of A-beta fibres are concentrated in the deeper dorsal horn and mainly target excitatory and inhibitory inter-neurons. However, the dorsal horn neuronal interconnections are modified and modulated under pathological conditions, such as peripheral nerve injury or peripheral tissue inflammation from injury or surgery [50–52]. Peripheral injuries may trigger on-going increases in the excitability of neurons (sensitization). This occurs at the level of the primary afferent nociceptive peripheral neuron (peripheral sensitization) and at the dorsal horn of the spinal cord (central sensitization). Reduction in the threshold for activation of nociceptive neurons is manifest as allodynia (a non-painful stimulus perceived as painful) and hyperalgesia (a mild painful stimulus perceived as severe or long-lasting pain). Allodynia or touch-evoked pain is A-beta mediated [53].
Complex interactions occur in the dorsal horn between afferent neurons, inter-neurons and descending modulatory pathways (see below). These interactions determine activity of the secondary afferent neurons. Glycine and gamma-aminobutyric acid (GABA) are important neurotransmitters acting at inhibitory inter-neurons.
Neuropathic pain may involve anomalous excitability in the dorsal horn, resulting from multiple functional alterations including; loss of function of inhibitory inter-neurons, reduced effectiveness of the inhibitory neurotransmitters, sprouting of wide dynamic neurons and activation of microglia, the immune cells of the CNS [54–56]. Microglia activate, respond and transform to reactive states through hypertrophy and proliferation [57, 58]. These activated microglia induce/enhance production and release of pro-inflammatory cytokines and brain-derived neurotrophic factor [59], which modulate the activity of dorsal-horn neurons [60].
“Wind up” is physiological activation in the spinal cord after an intense or persistent barrage of afferent nociceptive impulses [57, 61]. Central sensitization refers to enhanced excitability of dorsal-horn neurons and is characterized by increased spontaneous activity, enlarged receptive field areas, and an increase in responses evoked by large and small calibre primary afferent fibres. IASP taxonomy defines central sensitization as increased responsiveness of nociceptive neurons in the central nervous system to their normal or sub-threshold afferent input [2]. Secondary hyperalgesia (hyperalgesia in undamaged tissue adjacent to the area of actual tissue damage) is due to an increased receptive field and reduced threshold of wide dynamic neurons in the dorsal horn.
Central sensitization and wind-up intensify pain perception, and both depend on activation of N-methyl-d-aspartate (NMDA) receptors. Pain memories imprinted within the central nervous system by NMDA-receptor activation produce hyperalgesia and allodynia. NMDA glutaminergic synapses do not participate significantly in primary nociceptive transmission, but instead in spinal sensitization. NMDA blockade in the spinal cord does not prevent primary afferent transmission of nociceptive information to the thalamus. Therefore, any attempt to reduce pain needs to target nociception, as well as wind up and central sensitization.
The increased barrage of pain impulses secondary to peripheral and central sensitization confers change within the nervous system known as neuroplasticity. That is, the nervous system undergoes maladaptive changes in response to incoming pain signals by reorganizing its structure, function and connections. Patients with ongoing or chronic pain demonstrate such structural brain changes as well as abnormal functioning of the inhibitory pain-modulatory system [62]. In addition, in chronic-pain conditions, the primary brain areas accessed through classical acute pain pathways decrease in their activation incidence and pre-frontal cortex activity increases [63]. A simplified depiction of acute and chronic pain pathways is depicted in Figures 1 and 2. For more detailed information, please review “The Basic Science of Pain” by Philip Peng (https://itunes.apple.com/ca/book/the-basic-science-of-pain/id1174147456?mt=11).
Simplified acute pain pathways.
Simplified chronic pain pathophysiology.
When acute pain is not well-managed, deleterious effects on physiology, functional recovery and psychology can develop. Changes include increased morbidity such as nausea, emesis, poor oral fluid intake, sleep disturbance and behavioural changes. Ongoing discomfort and distress have a negative impact on child and family satisfaction and may be associated with poor recovery, anxiety, fear and reduced quality of life measures [64–71].
Physical and psychological responses to pain not only affect children’s health directly but may also predispose them to develop chronic post-surgical pain (CPSP). Chronic pain affects approximately 20% of the adult population of which 22.5% develop their condition after surgery [72]. CPSP occurs following 10–50% of adult operations in which 2–10% of these adult patients will experience severe chronic pain [73]. The incidence of CPSP in the adult population is found to depend on a number of perioperative factors, which include genetic predisposition, younger age, degree of pre-operative anxiety, degree of catastrophization, depression, pre-operative pain status, the surgical pain model, surgical technique, length of surgery and the quality of acute post-operative pain management [73–76]. CPSP will often be neuropathic, resulting from nerve damage during surgery. CPSP studies in children are limited with a preliminary incidence of CPSP reported as 13–25% [77–80]. Prospective studies after spine surgery have also demonstrated prevalence rates of CPSP between 11 and 22% with risk factor for development of CPSP including high levels baseline pain intensity, anxiety and older age [81–83]. Recently, Rabbitts et al. found two distinct pain trajectories following major surgery in children; most children follow a positive early recovery pathway, whereas 22% follow a late recovery trajectory. One of the factors of the late recovery group was the presence of baseline parental catastrophizing (not child/youth catastrophizing) [84]. Nikolajsen and Brix also identified factors for risk of CPSP in children as older age, pre-op pain, acute postoperative pain and psychological factors, especially anxiety [85]. Some of these children/youth will go on to develop chronic pain in adulthood [86]. All these complications of poorly managed acute pain ultimately increase healthcare utilization and have an economic cost for both families and the health-care service. It is, therefore, essential to minimize post-surgical pain to prevent pain-related complications. This may be achievable with the adoption of preventative multimodal analgesia to minimize nociceptive traffic and reduce wind up and central sensitisation.
Preventative analgesia is defined as analgesia that is provided by an intervention given in the perioperative period, which may be before or after incision and surgery, that reduces analgesic requirements for post-operative pain for a period longer than the duration of action for the analgesic intervention. Consideration needs to be given, not only to efficacy of analgesia regimens, but also that the duration pain management so that it spans the whole painful experience from incision to healing [87, 88]. Preventative analgesia differs from pre-emptive analgesia, where an analgesic intervention is administered pre-operatively with the aim to provide improved analgesia post-operatively compared with the identical analgesic intervention administered after incision or in the post-operative period [89].
Multimodal analgesia utilises combinations of analgesics that act by different modes to enable a reduction in analgesic requirements of each type of medication and therefore reduce side-effect profiles. The components of multimodal analgesia are shown in Table 1. A multimodal approach provides significant benefits, which include reduction in; pain intensity, opioid dose requirements, and opioid-related adverse events [68, 90–93]. In the acute perioperative pain setting, preventative multimodal analgesia is required not only to provide comfort but also to minimise the potential for “wind-up” and central sensitisation. Therefore, directly impacting, the mechanisms may induce the development of CPSP or chronic pain [94].
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Multimodal analgesia comprises a combination of the following modalities.
Although multimodal analgesia has been shown to be effective in reducing pain in children [95, 96], it should be remembered that many drugs used worldwide for paediatric pain management do not have approved labelling for use in children [97]. Drug dosing recommendations based on clinical evidence and experience, not based on evidence may well put children/youth at risk for medication-related adverse events [98].
A limited number of well-conducted, prospective randomized controlled trials have demonstrated improved clinical outcomes with respect to analgesia and opioid-related side effects with multimodal (vs. single) therapy [92, 93, 99]. However, there is an urgent need for research evaluating, which preventive multimodal analgesic regimens are most effective for different paediatric acute pain settings or surgical models of pain, the most appropriate timing of administration and which of these decrease or prevent long-term pain after surgery. In the meantime, paediatric acute pain teams need to develop surgery specific multimodal analgesia guidelines [100], assess effectiveness and respond quickly when the regime proves inadequate for an individual child/youth.
Good quality acute pain management enhances functional recovery, improves long-term functional outcomes [101] and improves patient and family satisfaction [93, 102].
Non-pharmacological techniques are an extremely useful component of multimodal therapy [103–105]; unfortunately, they are under-utilised in hospitalised children [106]. The mainstay of acute pain management for children and youths resides in the use of opioid analgesia, but opioid use is associated with a significant side effect profile (see Table 2). Adverse effects (except allergy) are dose-related and may be relieved by minimizing the opioid dose, conversion to a different opioid and/or using non-opioid adjuvants. IVLT is a useful adjuvant for specific acute pain procedures.
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Adverse effects of opioids.
Local anaesthetics are primarily used for local infiltration, nerve blocks and regional anaesthesia. Analgesia results from blockade of voltage-gated Na+ channels that prevent action potential initiation and propagation. Local anaesthetics impede sodium ion access to the axon interior, probably by physically occluding the trans-membrane sodium channels. This is a reversible process, which does not damage the nerve. Depolarization cannot take place when the sodium channel is blocked, so the axon remains polarized. A local anaesthetic regional or nerve block is, therefore, a reversible, non-depolarization block. In contrast, systemically administered local anaesthetics produce analgesia at plasma levels well below that required to block an action potential. Systemic administration of local anaesthetic is most recognized with lidocaine due to its widespread use for anti-arrhythmic treatment [113–115].
Lidocaine is an amide local anaesthetic and a Class Ib cardiac anti-dysrhythmic agent [116]. Therapeutic plasma levels and duration of IVLT for acute pain management are not well defined, although the optimal therapeutic range for acute pain treatment appears to be between 1 and 5 μg/ml [6, 24, 117–120]. Only preservative free formulations should be given intravenously. Bolus administration of 2 mg/kg and a continuous infusion of 2–5 mg/kg/h have shown to reach plasma levels of 1–4 μg/ml [121]. After a bolus injection or continuous administration for up to 12 h, the half-life of lidocaine is about 100 minutes and shows linear pharmacokinetics [122].
Lidocaine metabolism occurs rapidly in the liver by cytochrome P450 isoforms CYP1A2 and 3A4, as outlined in Figure 3. Lidocaine undergoes oxidative N-dealkylation, to a number of metabolites that include monoethylglycinexylidide (MEGX) and glycinexylidide (GX), and N-ethylglycine (NEG), all of which have a glycine-like moiety. Less than 10% of lidocaine is excreted unchanged by the kidneys. MEGX is an active metabolite and has 80% potency of lidocaine at VGSC’s. GX is also active but NEG is inactive. Following intravenous administration, MEGX concentrations in serum range from 11 to 36% of the lidocaine concentration. All lidocaine metabolites are excreted by the kidneys. The half-life of lidocaine elimination from the plasma following IV administration is 81–149 min (mean 107 ± 22 SD,
Lidocaine metabolism.
In infants less than 6–7 months of age liver metabolism is immature so metabolism of drugs is delayed, and plasma protein levels are lower [124]. There are low levels of plasma alpha-1-acid glycoprotein, which increases the free fraction of circulating lidocaine and therefore increases the risk of toxicity [125]. IVLT in high doses (6–8mg/kg/h without a bolus dose) has used to treat neonatal seizures but the risk-benefit indication is considerably different than for pain management [126]. For these reasons, IVLT for pain management cannot be recommended in infants until more evidence of efficacy and safety in this population are available.
A major advantage with IVLT is that appropriate use in adults is not associated with a significant side-effect profile [7, 127, 128]. In adults, a 100 mg bolus followed by an infusion at 1 mg/min, which approximates to 1mg/kg/h, produces a plasma level of just over 1 μg/ml in normal individuals with no co-morbidities [129]. IVLT doses used to manage pain are usually in the range of 1–2 mg/kg/h. Plasma levels at this rate of infusion are generally less than 3–5 μg/ml, but awake patients may complain of light-headedness, perioral numbness, dizziness and or sedation. Toxic plasma lidocaine levels are considered to be in the >6 μg/ml range [130]. Early signs of local anaesthetic systemic toxicity (LAST) will present as perioral numbness, metallic taste, tinnitus, visual and auditory disturbances, paresthesias, nausea, dizziness and drowsiness [7, 131–133]. Due to the short half-life of lidocaine, the symptoms of LAST are easily reversible by lowering or discontinuing the infusion. To provide some perspective, lidocaine effects at higher plasma levels are more serious; at 8 μg/ml, patients experience visual or auditory disturbances, dissociation, muscle twitching, and decreased blood pressure. At 12 μg/ml, convulsions can occur; at 16 μg/ml, coma may develop, and at levels above 20 μg/ml respiratory arrest and cardiovascular collapse ensue [132]. Physicians administering IVLT must be aware of algorithms of care to prevent, recognise and treat LAST when it occurs [134].
Contraindications to IVLT include allergy to amide local anaesthetics, significant cardiac disease, heart block, seizures, liver disease and/or significant renal impairment.
Studies in animal preparations clearly indicate that systemically administered lidocaine can silence ectopic discharges without blocking nerve conduction [135, 136]. Systemic administration of local anaesthetics provides clinical analgesia in a broad range of neuropathic pain states [23, 117, 137–140]. IVLT induces global analgesia and dampens the neuro-inflammatory response in pain [126, 141–144]. Lidocaine exerts its different effects on the neuro-inflammatory response by inhibiting ion channels and receptors. The exact lidocaine plasma level and duration of infusion required to produce this effect are unknown; however, it occurs at levels below those required for action potential initiation and propagation for neural blockade. It is also not known if plasma lidocaine concentration correlates with analgesic effect in a dose dependent manner as different channels and receptors are modulated at different plasma lidocaine concentrations [145].
Intravenous lidocaine has peripherally and centrally mediated analgesic, anti-inflammatory and anti-hyperalgesic properties. Its analgesic properties reflect the variable dose, time dependent, multimodal aspect of its action on voltage-gated channels receptors and neurotransmitters that affect nociceptive transmission pathways [24, 45, 146–148]. In vitro, low dose lidocaine inhibits voltage-gated sodium channels (VGSC), some potassium channels, the glycinergic system, and G-protein coupled receptors. Higher dose lidocaine blocks voltage-gated calcium channels, other potassium channels, and NMDA receptors [145, 149, 150]. Lidocaine dosages needed for voltage-gated sodium channel blockade range from 60 to 200 μM, whereas voltage-gated calcium channel blockade occurs at higher doses in the 1–10 mM range [6, 151–153]. A number of different sodium channel isoforms exist with distinct tissue distribution and possibly distinct physiological functions. Some of these isoforms have been shown to be up-regulated in inflammatory and neuropathic pain states [28, 154–156]. Lidocaine blocks all sodium channel isoforms but differences in isoform sensitivity to lidocaine could be an explanation for efficacy in various different pain models.
Animal studies demonstrate that systemic lidocaine changes conduction in neurons of the dorsal horn, dorsal root ganglion and hyper-excitable neuromas without affecting normal nerve conduction [23, 135, 157]. Cell membranes of injured peripheral nerves express sodium channels with unusual density and produce persistent spontaneous discharges that maintain a central hyper-excitable state [20]. Ectopic discharges can be initiated along the injured nerve, in the dorsal root ganglion, and in peripheral neuromata [157–161]. Lidocaine inhibits these aberrant electrical discharges at concentrations well below those necessary to produce conduction blockade in nerves. Dorsal-horn neurons are more sensitive to lidocaine compared with peripheral neurons [135]. The high susceptibility of hyper-excitable neurons to lidocaine may be attributed to the changed expression of sodium channels during nerve injury [28].
Analgesic effects are thought to be mediated by the inhibition of Na channels, NMDA, and G-protein-coupled receptors that lead to the suppression of spontaneous impulses generated from injured nerve fibres and the proximal dorsal root ganglion [23, 117, 159, 162].
While the main mechanism of the therapeutic action of lidocaine is considered to be blockade of voltage-gated channels, lidocaine may also have a desensitizing effect on TRP channels. This may reflect the prolonged analgesic effects sometimes seen that outlast the expected presence of lidocaine in the tissue [163].
Anti-inflammatory effects are attributable to attenuation of neurogenic inflammation and subsequent blockade of neural transmission at the site of tissue injury. Lidocaine inhibits the migration of granulocytes and release of lysosomal enzymes which leads to decreased release of pro- and anti-inflammatory cytokines [146, 162, 164–167]. Animal studies demonstrate that these anti-inflammatory effects of lidocaine are mediated by inhibition of VGSC, G-protein-coupled receptors and ATP-sensitive potassium channels.
The anti-hyperalgesic effect of lidocaine is presumed to result from the suppression of peripheral and central sensitization through a combination of nocioceptor blockade, dampening of the neuro-inflammatory response to pain, NMDA receptor inhibition and modulation of the glycinergic system [25, 168–173]. Low dose lidocaine (10 μM) enhances and high dose (1 mM) inhibits glycinergic signalling [174]. The lidocaine metabolite, N-ethylglycine (NEG) is a substrate of the glycine reuptake transporter so it competes with endogenous and synaptically released glycine for reuptake leading to increased extracellular and synaptic glycine levels [172]. This would explain why NEG has been shown to induce analgesia in rodent models of neuropathic and inflammatory pain but has minor effects on Na+ channels [172]. The lidocaine metabolite MEGX has been shown to inhibit the glycine transporter which will also increase glycine levels [172].
On-going input from peripheral nociceptors which is blocked by local anaesthetics is used to explain dependence of pain syndromes on peripheral inputs [175]. However, IVLT also has a central effect reducing components of pain caused by central nervous system injuries [176]. Systemically administered lidocaine has been shown to suppress capsaicin-induced hyperalgesia by a central mode of action, whilst concurrently reducing acute chemically induced pain by a peripheral mode of action [114]. Descending facilitatory pain transmission from the rostroventromedial medulla may also be suppressed by lidocaine [177, 178].
Lidocaine infusions were described to be effective in the relief of acute post-surgical pain as early as 1961 [179]. Since then many other studies have confirmed the analgesic effects of lidocaine in patients with acute pain, such as Stayer’s report on the safe and successful use of continuous pleural lidocaine after thoracotomy in children [180]. In 2012, Sun et al. published a meta-analysis of randomized controlled trials examining systemic lidocaine for post-operative analgesia and recovery after abdominal surgery [181]. It showed a decrease in post-operative pain intensity, opioid consumption, time to first bowel movement, and hospital length of stay. The most widely used lidocaine infusion regimen was a bolus of 1.5 mg/kg lidocaine followed by an infusion of 1.5–2 mg/kg/h.
The current evidence for using IV lidocaine for perioperative pain is based on four systematic reviews and one Cochrane review [128, 182–185]. In the most recent Cochrane review Kranke et al., reviewed only perioperative studies where the IVLT had been started intra-operatively prior to incision and continued at least until the end of surgery. Forty studies met the inclusion criteria. Primary outcomes measures required were pain score (0–10 cm, 0–100 mm visual analogue scale, (VAS), numeric rating scale (NRS), post-operative ileus, and functional gastrointestinal recovery (either time to defaecation, time to first flatus, or time to first bowel movement/sounds). Secondary outcomes sought included length of hospital stay, functional post-operative neuropsychological status scales, surgical complications (such as post-operative infections, thromboembolism, wound breakdown), patient satisfaction (satisfaction survey), cessation of the intervention, intra-operative opioid requirements, opioid requirements during the postoperative period and any adverse events (e.g. post-operative nausea and vomiting (PONV), death, dysrhythmias or signs of lidocaine toxicity).
Intravenous lidocaine administration was initiated with a bolus dose in 64% of the included trials. The subsequent infusion ranged from 1 to 3 mg/kg/h but most commonly was 1.5 mg/kg/h. In five studies, no bolus dose was given prior to the start on the intravenous infusion of lidocaine [186–190].
The lidocaine infusion was terminated either at skin closure or the end of the surgical procedure [45, 186, 188, 190–206]; 1 h after surgery/skin closure [207–212]; 1 h after arrival in the post anaesthesia care unit (PACU) [213]; 4 h post-operatively [214]; up to 8 h post-operatively (or at PACU discharge whichever occurred earlier) [187]; after a total of 12 h [215]; 24 h post-operatively [216–223]; 48 h post-operatively [215, 224–226]; or on the day of return of bowel function or, at the latest, on the fifth post-operative day [189]. One study did not report the cessation time for the lidocaine infusion [227].
In this review, intravenous lidocaine was used in a variety of surgical procedures such as abdominal surgeries, tonsillectomy, orthopaedic, cardiac, and ambulatory surgeries. It was found to be useful only in abdominal surgery, where anaesthetic and opioid requirements were significantly reduced in the perioperative period. Several studies reported a decrease in pain intensity (pain at rest, cough, and movement), opioid requirements, and opioid-related side-effects, such as PONV. A decrease in the duration of post-operative ileus was also seen and is attributed to a combination of opioid-sparing effect, anti-inflammatory actions, decreased sympathetic tone and the direct effect of lidocaine on intestinal smooth muscle. These benefits did not translate to expedited discharge from PACU nor have a positive effect on ambulatory surgeries.
None of the studies included in the most recent Cochrane review for IVLT in acute pain management were paediatric. There is currently only one randomized controlled trial of IVLT in a paediatric acute pain population [228]. This study demonstrated decreased hospital stay, decreased rescue analgesia requirements, decreased cortisol levels and earlier return of bowel function with IVLT (1.5mg/kg bolus followed by 1.5mg/kg/h infusion) compared to placebo followed abdominal surgery. Until further evidence of paediatric analgesic efficacy and safety are available doses have to be translated from adult practice. It is not clear what dose regime and plasma concentration provide the best analgesic efficacy for particular surgical models of pain. Pain management remains an off-label indication for the use of IVLT, and the paediatric continuous infusion dosing quoted in the drug information documentation (0.5–3 mg/kg/h) refers to its use as an anti-arrhythmic agent.
The author uses IVLT as an adjunct in preventative multimodal analgesia for major paediatric (non-infant) surgical procedures where a regional or neuraxial analgesia technique has to be avoided or is contra-indicated. Typical procedures include scoliosis surgery, laparoscopic abdominal surgery and external frame fixator procedures. Lidocaine infusion regimes are typically 1 mg/kg bolus dose followed by an infusion with 2 mg/kg/h started prior to incision and continued until just after surgical closure. With extensive surgical times, the IVLT is decreased to 1.5 mg/kg/h after 8 h. It is essential to understand that there is little data to confirm the appropriate dosing and safe lidocaine levels in the paediatric population. However, clinical evaluation would suggest that the use of intravenous lidocaine therapy, in this manner, has beneficial effects on paediatric post-operative pain, opioid requirements and child/youth sense of wellbeing, especially in the first 24 h. In an attempt to determine appropriate research questions and outcome measures we have retrospectively reviewed 24 paediatric scoliosis cases. Twelve children undergoing idiopathic scoliosis correction (posterior instrumentation and fusion only) between January 2012 and March 2014, where intra-operative IV lidocaine infusion was administered were compared against twelve matched controls. The lidocaine group received a total dose of 14.17 ± 2.39 mg/kg, given over 6.45 ± 0.74 h. Both groups were comparable with respect to age, gender, body mass index (BMI), number of levels instrumented and surgical duration. Morphine consumption within the first 48 h post-operatively was significantly lower in the IVLT group [229]. Despite the small sample size and the retrospective nature of this case matched chart review the significant opioid-sparing effect in the post-operative period with the use of intra-operative IV lidocaine infusion merits further study. Prospective, randomized controlled trials are recommended.
In many studies, the analgesic effect has persisted after the lidocaine infusion was discontinued, which suggests prevention of peripheral and/or central hypersensitivity [209, 211]. Perioperative lidocaine has been found to have a preventive effect on post-operative pain for up to 72 h after abdominal surgery [211]. A randomized, double-blind, placebo-controlled study of 36 adult patients undergoing breast cancer surgery showed that perioperative intravenous lidocaine (bolus of IV lidocaine 1.5 mg/kg followed by a continuous infusion of lidocaine 1.5 mg/kg/h) was associated with decreased incidence and severity of chronic pain after breast surgery. Two (11.8%) patients in the lidocaine group and 9 (47.4%) patients in the control group reported CPSP at 3 months follow-up (
Chronic pain is pain that persists for more than 3 months and often years beyond the expected time to heal from injury, surgery or onset of a painful condition. It occurs in one in five adults and is a significant cause of suffering and disability worldwide. Although mainly a disease of adults, it does occur in children and youths with slightly more than one child/youth in every twenty reporting a chronic pain issue. A Canadian study of 495 schoolchildren aged 9–13, reported that more than half reported having experienced at least one recurrent pain (headache, stomach pain or ‘growing pains’). 46% of this population reported a ‘long-lasting’ pain, however, the authors classified 6% as having chronic pain [230]. A Statistics Canada health report identifies chronic pain among 2.4% of males and 5.9% of females aged 12–17 years [231].
Typical types of chronic pain seen in children and youths include headaches, complex regional pain syndrome (CRPS), recurrent abdominal pain, limb and other musculoskeletal pains. Girls are three times more likely to report chronic pain than boys [232, 233]. Abdominal pain is significantly more likely to be reported by girls and limb pain (or growing pains/muscle aches) is significantly more likely to be reported by boys [230, 233, 234]. Although prevalence of chronic pain in school children varies from 9 to 32% [235, 236] and is on an increase [234], the reported prevalence exceeds the prevalence of school aged children seeking medical care for pain [237]. Cross-sectional and/or retrospective studies may not reflect the true picture and call for more longitudinal research to establish the actual prevalence and impacts of ongoing pain in children and youths has been advocated [238].
Some children with severe chronic pain embark on a downhill spiral of decreased physical, psychological and social functioning [239]. This includes loss of mobility with inability to participate in physical or sporting activities, poor sleep, difficulty concentrating on school work, school absenteeism, social isolation and family stress [240]. As chronic pain persists, the child can experience increased pain intensity, distress, sadness, anxiety, depression resulting in very poor quality of life [241]. The impact of chronic pain on the family matches the adverse impact experienced by families caring for children at home with severe cerebral palsy or birth defects [242–244]. Direct and indirect costs such as loss of earnings, adaptations to housing, over-the-counter medications and care assistance managing a child with chronic pain are considerable [245–248].
When entangled in the disordered lifestyle associated with chronic pain the child/youth and their family require coordinated integrated care to affect a recovery. The multi-disciplinary team management approach, based on pharmacology, physiotherapy and psychology (the 3P approach), is now well established to be the standard of care for children with chronic pain. This method involves looking beyond a child’s pathology in isolation and engages multiple specialists to optimize the child/youth’s psychological and emotional wellbeing, physical function and pharmacological therapy [247, 249–251]. This process requires adoption of a self-management approach and reduced reliance on medical investigation and intervention. Children and youth with significant pain-related disability have been shown to derive significant improvements in functional ability after participating in an intensive pain rehabilitation program employing daily physical, occupational and psychological therapies [247, 248, 252, 253].
Multi-disciplinary treatment goals are targeted to each individual child/youth after careful consideration of the medical history, pain history, examination and relevant investigations. How each therapeutic modality of care is balanced is dependent on the individual child and takes into consideration the type and duration of pain, as well as the impact of pain on particular biopsychosocial aspects of the child’s life. Early recognition and appropriate ‘3P’ management is the key to success. Within the context of the coordinated multi-disciplinary approach, IVLT can serve as a useful adjunct to concurrent physical, and psychological interventions to manage chronic pain in children and youths [133, 254, 255]. IVLT needs to be explained and utilized in a way that does not negate the multi-disciplinary teams attempts to promote self-management and de-medicalization.
Determining or predicting suitability for successful pharmacological treatment requires attention to a number of factors. It is essential to consider any available evidence (often lacking especially in the paediatric population), drug responsiveness (matching the predicted mechanism of action of the drug with the pathophysiology of the pain condition), side effect profile, goals of therapy and the possible impact of the pharmacological intervention to the holistic plan of self-management and return to function for the individual child/youth. One of the goals of therapy is a shift away from a change in the pain rating and pain responsiveness to restoration of physical and social functioning. For some children pharmacological therapy is not required to achieve this goal. Timing of pharmacological intervention is also important. For some children ensuring that self-management strategies and attempts at return to function are initiated prior to pharmacological intervention may decrease a reliance on medications to initiate or promote change. Not all children and youths will have a predictable or positive response to the types of medications used in chronic pain. Some will require a trial of more than one type of pharmacological agent. To minimize side-effect profiles only the lowest effective dose should be used. Different pharmacological agents may have to be used in a tiered proportional manner, balancing risk versus benefits but with the over-riding aim to improve quality of life. As the simplest most appropriate pharmacological strategy should be trialled first it is important to briefly discuss topical lidocaine.
For the purpose of this review topical lidocaine refers to q12h 5% lidocaine patch or compounded 5% lidocaine applied under an occlusive dressing (12 h on, 12 h off) administered daily. Topical lidocaine should only be applied to intact skin over a localised painful area. It is assumed that topical lidocaine works by blocking sodium channels on C, A-delta [256] and A-beta nerve fibres [257]. Allodynia is a prominent component of neuropathic pain, which is A-beta mediated and driven by central sensitization [80]. Topical lidocaine reduces nociceptor discharge at the level of the skin, to enable a light mechanical stimulus to induce a sense of touch, not pain. The analgesic effects of topical lidocaine probably do not require anaesthesia to the skin [258]. When lidocaine patches are used according to the recommended dosing instructions, only 3 ± 2% of the dose applied is expected to be absorbed. Repeated application of three lidocaine patches, used for 3 days simultaneously (12 h on, 12 h off), indicates that the lidocaine concentration does not incrementally increase with ongoing daily use. Pain relief from topical lidocaine occurs despite the extremely low systemic lidocaine plasma levels achieved. These plasma levels range from 0.13 to 0.23 μg/ml [259, 260], which is approximately one-tenth of the effective level obtained with IVLT. Despite this, neuropathic pain patients achieve pain relief from topical lidocaine [259, 261–267]. Lidocaine patches also produce analgesia in patients with painful diabetic neuropathy [268], Complex regional pain syndrome (CRPS) [269] and non-neuropathic conditions such as osteoarthritis and low-back pain [261, 270–273]. Systemic side effects are extremely rare and topical lidocaine is therefore recommended as a first-line therapy for all children and youths with localized peripheral neuropathic pain or CRPS and definitely before consideration of IVLT.
Lidocaine’s short serum half-life of 120 min dictates that the analgesic effect disappears a few hours after treatment so this should completely preclude its use for chronic pain issues. However, prolonged relief has been reported in animal models [274] and in some non-randomized [255, 275] and randomized trials [175, 276, 277]. The Canadian Pain Society states that “intravenous lidocaine infusions are generally safe and can provide significant pain relief for 2–3 weeks at a time” [278]. The 2012 neuropathic pain interventional guidelines by Mailis and Taenzer issue a Grade B recommendation for IV lidocaine at 5–7.5 mg/kg, with relief expected to last in the range of hours to 4 weeks [279]. Clinical studies show analgesic effects of intravenously administered sodium channel blockers especially in pain conditions where hyperalgesia is prominent [114, 139, 143, 144, 276, 277, 280–282]. Chronic pain conditions, in which reports of IVLT have been beneficial include peripheral nerve injury [283], neuropathic pain [7, 16, 274, 276, 279, 284–286], CRPS [255, 287], headaches [133, 288, 289], cancer therapy, spinal cord injury [176] and fibromyalgia [290].
There is a distinct lack of evidence to support the use of IVLT for paediatric chronic pain management. Criteria and dosing guidelines are institutionally formulated based on clinical experience, but equate with dose regimes previously reported to manage chronic pain in adolescents and young adults [133], see Table 3.
1. | Child/youth is fully integrated into multi-disciplinary care |
2. | Their pain syndrome is considered to be lidocaine-responsive |
3. | The pain is not amenable to the use of topical lidocaine |
4. | Patients have no contra-indication to the use of systemic lidocaine such as major cardiac dysfunction, liver dysfunction, renal impairment, seizure activity, or allergy to amide local anaesthetics |
5. | Child/youth capable of verbally communicating analgesic response and symptoms of potential local anaesthetic toxicity. |
6. | A high-acuity environment capable of providing continuous ECG monitoring, oxygen saturation, and frequent blood pressure measurements, plus access to healthcare personnel skilled in resuscitation and airway management. |
BCCH institutional selection criteria for initial IVLT in children/youth.
Initial infusion:
Location: post-anaesthetic care unit
Monitors: as dictated by CPSBC guideline
Loading dose: 1 mg/kg bolus
Infusion: 5 mg/kg delivered over 1 h
Total dose: 6 mg/kg (loading dose + infusion)
IVLT should only be administered within a high-acuity environment such as a paediatric intensive care unit, high-acuity unit, step-down unit, or post-anaesthetic care unit.
The College of Physicians and Surgeons of British Columbia published out of hospital Pain Infusion Clinic guidelines in 2014. The guidelines are intended only for the treatment of adults, and to the best of our knowledge, no such guidelines exist for the paediatric population. Of note, they require two appropriately trained nurses or one anaesthesiologist plus one nurse to be present in the room at all times during a lidocaine infusion, as well as one-to-one nursing for the first hour of the infusion. If the patient remains stable and not overly sedated, then the nursing ratio can be dropped to one nurse per two patients. An anaesthesiologist must be present on site until the patient is suitable for discharge. Required equipment includes an ECG monitor, suction, oxygen source and delivery systems, intravenous supplies, emergency medications, a light source, and emergency power and lighting. Lidocaine infusions are to be administered by a programmable device with a locked control panel and delivered via a dedicated intravenous line. Loading doses are to be given only by an anaesthesiologist. Patient and vital sign monitoring should be performed every 5 min for the first 15 min, every 15 min for the next 45 min, and then every hour until the infusion is complete, then 30 min after discontinuation of the infusion [291].
There is also a distinct lack of evidence to support the use of repeated IVLT for chronic pain management. The following criteria and dosing guidelines are also institutionally formulated based on clinical experience, see Table 4.
1. | Child/youth is fully integrated into multi-disciplinary care |
2. | The pain syndrome is lidocaine-responsive based on previous lidocaine infusion. |
3. | The pain is not amenable to the use of topical lidocaine |
4. | The child/youth demonstrates some improvement in functional activity following on from previous lidocaine infusion |
5. | Child/youth has no contra-indication to the use of systemic lidocaine such as major cardiac dysfunction, liver dysfunction, seizure activity, or allergy to amide local anaesthetics. |
6. | Child/youth capable of verbally communicating analgesic response and symptoms of potential local anaesthetic toxicity. |
7. | A high-acuity environment capable of providing continuous ECG monitoring, oxygen saturation, and frequent blood pressure measurements, plus access to healthcare personnel skilled in resuscitation and airway management. |
BCCH selection criteria for repeat systemic lidocaine therapy in child/youth.
Second infusion:
Location and monitors as for initial infusion
Loading dose: 1 mg/kg bolus
Infusion increased to 7 mg/kg over 90 min
Total dose: 8 mg/kg (loading dose + infusion)
Time between infusions: usually a month
Third infusion:
Location and monitors as above
Loading dose: 1 mg/kg bolus
Infusion increased to 9 mg/kg over 90–120 min
Total dose: 10 mg/kg (loading dose + infusion)
Time between infusions: usually a month
If IVLT is effective or partially effective, the patient can be started on a 5-day continuous subcutaneous (SC) infusion if pain is hampering for restoration of function/physical activity (Table 5). SC infusions use an elastomer pump which delivers a set volume of lidocaine per hour (depending on the pump used), usually 5 ml/h, which approximately equates with 2 mg/kg/h using 2% lidocaine for a patient who is 50 kg. The infusion only runs whilst the patient is awake so that they can self-report any symptoms, which may suggest lidocaine toxicity.
1. | Child/youth is fully integrated into multi-disciplinary care |
2. | Their pain syndrome is lidocaine-responsive. |
3. | The pain is not amenable to the use of topical lidocaine |
4. | Child/youth has no contra-indication to the use of systemic lidocaine. |
5. | Child/youth capable of verbally communicating analgesic response and symptoms of early local anaesthetic toxicity. |
6. | The child has previously experienced a lidocaine infusion in a high acuity environment without complication. |
7. | The child/youth demonstrates some improvement in functional activity following on from previous lidocaine infusion/s. |
8. | The child/youth and their principal carer demonstrate the ability to follow safety instructions. |
9. | Appropriate homecare support, immediate telephone contact with healthcare team and follow-up are in place. |
BCCH selection criteria for subcutaneous lidocaine therapy in child/youth.
Of 336 new children/youth seen as out-patients by one pain physician in our institution over a 6.5 year time frame, only 45 (13%) were considered appropriate for trial of IVLT; 36/45 (80%) of these patients were females. The diagnoses, IVLT treatments and outcomes for these 45 children/youth are shown in Tables 6 and 7.
Diagnosis | |
Complex regional pain syndrome (CRPS) | 24 (53%) |
Neuropathic pain | 7 (16%) |
Headaches | 4 (9%) |
Diffuse muscular/whole body pain | 4 (9%) |
Other | 6 (13%) |
IVLT sessions | |
1 IVLT session only | 19 (42%) |
2 IVLT sessions | 19 (42%) |
3 IVLT sessions | 6 (13%) |
4 IVLT sessions | 1 (2%) |
Diagnoses and number of IVLT treatments received as part of 3P treatment package.
Improved outcome reported | Success ratio* |
---|---|
Physical functioning | 32/43 (74%) |
Pain | 32/45 (71%) |
Mood related to pain | 22/31 (71%) |
School | 16/26 (62%) |
Sleep | 17/29 (59%) |
Social functioning | 8/21 (38%) |
Improved outcomes reported by patients following 3P treatment including intravenous lidocaine therapy (IVLT).
Number of patients reporting improvement / number reporting issue prior to treatment.
It is clear that not all children and youth with chronic pain are candidates for IVLT. Focus should be on pain conditions with a neuropathic or central element. However, when appropriately selected, and integrated in multi-disciplinary care, IVLT can be part of the reason that children and youth experience less pain facilitating healthier sleep, improved physical activities, and return to school. It is also clear that not all children/youth considered appropriate for IVLT respond positively. This needs to be clearly outlined with a plan of management prior to embarking on an IVLT therapy.
The specific effects of IVLT rely on the pharmacological action of lidocaine. However, other elements of care are also critically important especially the psychosocial dynamics of the diagnosis and treatment process. Three mechanisms contribute to improvement in a patient’s pain or functioning; the specific or intended effects of treatment, natural history of the disease and non-specific effects of treatment [292].
One non-specific treatment effect likely to improve treatment outcomes is high pre-treatment expectations of recovery [293–299]. Factors shown to modulate pre-treatment expectations include dispositional optimism [300–302], sex [297, 303], age [303], education level [297, 303], clinician-patient interactions [304] and degree of psychological distress [297]. Expectations can be enhanced by verbal suggestions, conditioning and imagery [299]. Influences likely to improve treatment outcomes include high expectations, no pre-existing mood disorder, low levels of anxiety, acceptance of the chronic pain diagnosis, a desire to get better, a need to return to a previous level of functioning, motivation and good clinician-to-child relationship and trust in the healthcare team.
Children and youth with chronic pain will require a lot of effort on the part of the clinicians to establish trust as they have met with many previous different healthcare workers; they may have been given mixed messages regarding the aetiology of pain, and potentially exposed to a negative encounter (not feeling believed that they have pain, lack of empathy, poor communication, lack of appropriate help).
To gain a child or youth’s trust and that of their parents requires good communication [304–306]. This demands devotion of enough time to listen and extract a precise pain history, use of appropriate language and terminology, developmentally appropriate explanation of concepts [307] as well as understanding family culture, beliefs, hopes and fears. Trust necessitates that; potentially embarrassing questions are asked separately and in confidence and that the healthcare team convey empathy and expertise/credibility in chronic pain management. Introducing appropriate humour into the dialogue also helps to establish good rapport. It is also important to explain to a child/youth with ongoing pain that the healthcare team will attempt to minimise any pain on examination. During the initial assessment good education, establishing an agreed workable goal-directed and achievable management plan positively alters patient outlook as well as responses to treatment [298, 308]. Communicating positive expectations of treatment also contributes to decreased pain and improved functioning [309–311].
Psycho-social effects such as sadness, frustration, anxiety, anger, catastrophization or depression are the detrimental factors that are associated with continuation or worsening of pain. If these psychological factors remain unrecognized and untreated, they become barriers to the onward progress of any chronic pain management plan.
Without the evidence of a randomised double-blind placebo controlled trial, it is not easy to discern the over-riding beneficial therapeutic modality in the chronic pain case series presented. It could be argued that IVLT responsiveness, in tandem with good rapport and trust in the healthcare team, represents a placebo response. Such a response is defined as ‘the psychobiological response seen after administration of a non-therapeutic modality’. Placebo treatments have known effects on endogenous pharmacology, as well as the cognitive and conditioning systems in humans [312–319]. The placebo response rate is higher in children compared with adults [320, 321]. Patient expectations and the doctor-patient relationship contribute to placebo analgesia responses and are unique to the individual [322]. The respiratory centres, serotonin secretion, hormone secretion, immune responses and heart function are also involved in the biological response to placebo analgesic treatments [319]. There is evidence that endogenous endorphins play a role as some placebo analgesic responses are reversed with naloxone [318, 323]. When considering non-analgesia placebo responses, dopamine also plays a major role [324]. Placebo response, or not, IVLT is a short intervention with minimal side effect profile, it is a worthwhile component of therapy that helps effect a turnaround to recovery in a child or youth who may have had pain and disability for many months prior to the intervention.
In an effort to increase the effectiveness of multi-disciplinary pain programs, more research is needed to further investigate pharmacological advances, psychological therapies and physiotherapy techniques that work for different ages, different types of pain and at different times in the chronic pain journey. It is clear that we also need to research and adopt clinical strategies aimed at optimising placebo and non-specific treatment effects in the paediatric population.
Intravenous lidocaine has peripherally and centrally mediated analgesic, anti-inflammatory and anti-hyperalgesic properties [176] with minimal side-effect profile if used at appropriate dosing in properly selected children/youths. It is ideally placed to be a useful adjunct in perioperative pain management to improve comfort, reduce opioid requirements and reduce the attendant opioid side effect profile.
The analgesic properties reflect the variable dose, time dependant, multimodal aspect of its action on voltage-gated Na channels and other receptors that affect nociceptive transmission pathways [23, 24, 45, 117, 146–148, 159, 162]. The anti-inflammatory effects of lidocaine are attributable to attenuation of neurogenic inflammation and subsequent blockade of neural transmission at the site of tissue injury [146, 162, 164, 165, 167].
The anti-hyperalgesic effect of lidocaine, through suppression of peripheral and central sensitization also diminishes the neuro-inflammatory response to pain [25, 168–171, 173, 325]. A basic understanding of pain physiology and pathophysiology is essential to understand how these three beneficial components of IVLT are effecting this response.
Evidence from adult work and clinical experience with paediatric patients indicates that IVLT is a modality, which needs to be considered for major surgical procedures where a regional technique is not indicated. This has promise to improve post-operative pain, reduce opioid requirements and prevent central sensitisation. More work needs to be done to demonstrate effective dose response and plasma levels of lidocaine that are associated with analgesic efficacy for different surgical pain models and whether continuation of the infusion into the post-operative phase will further reduce acute or chronic postsurgical pain.
Chronic pain of childhood is an extremely complex condition that can have devastating effects on physical, psychological and social functioning. The inter-disciplinary team management approach, based on pharmacology, physiotherapy and psychology, is the standard of care for children with severe or ongoing chronic pain. IVLT is a modality that may be considered when the history and examination findings confirm a central, neuropathic or CRPS aspect of the presenting pain. The current lack of evidence-base to support this recommendation does necessitate full disclosure of risks and benefits for informed consent and shared decision making to occur. IVLT must be explained in the right context as a small part of the multi-disciplinary care package, which focuses on de-medicalization and self-management. A singular focus on reducing pain intensity without considering improvement in physical activity, social functioning and overall quality of life is distinctly misguided. Treatment expectations need to be clear that IVLT is used to improve comfort to enable physiotherapy/physical functioning to go ahead and needs to be performed in tandem with all the other multi-disciplinary aspects of care.
Pain clinicians need to engage in large multi-site randomised controlled trials to provide the evidence-base to determine that IVLT is indeed an effective and safe treatment option in acute preventative multimodal analgesia and as an adjunct in the multi-disciplinary care of chronic pain in the paediatric population.
Nick West for his help with preparation of this chapter. Dr. T. Oberlander and Dr. C. Montgomery for their helpful reviewer comments.
Stroke is the leading non-communicable disease worldwide and in the Southeast Asia (SEA) region [1]. In Bangladesh, stroke is the second leading non-communicable disease in terms of the cause of death and long-term disability. Those who survived from stroke attack need quality rehabilitation services to maintain their health and prevent them from death due to the second episode of stroke attack [2]. The quality of services can be viewed from many perspectives. However, the patient perspective is now given more importance because it can lead to the effectiveness of healthcare services and better health outcomes. Therefore, this study aims to examine the level of patient expectations and perceptions and the factors relating to the patient expectations and perceptions of outpatient post-stroke rehabilitation services delivery management in Bangladesh.
This chapter includes an overview of Bangladesh, health status and challenges, stroke definition and situation, post-stroke situation and how Bangladesh healthcare service systems respond to the post-stroke, stroke, and post-stroke care pathway and quality of post-stroke rehabilitation services as well as the methodology to examine the quality of post-stroke rehabilitation services and conceptual framework of this research study.
Bangladesh is one of the smallest and most densely populated countries in the world. It is a developing country and a founding member of the South Asian Association of Regional Cooperation (SAARC) to promote regional connectivity and cooperation. Additionally, it is a member of the Commonwealth of Nations [3].
Bangladesh is a country in the South Asia Region [3]. According to the Ministry of Health and Family Welfare [4], geographically it is divided into eight divisions/provinces, and the total land area of this country is 147,570 sq. km. Dhaka division is the central division, and Dhaka city is the capital city of Bangladesh followed by Rajshahi, Barishal, Chittagong, Sylhet, Mymensingh, Khulna, and Rangpur divisions. Bangladesh National Portal [5] reported that the divisions/provinces are divided into 64 districts and 11 metropolises. Under the districts, there are 491 sub-districts. The sub-districts contain 4553 union councils in the rural areas and 323 municipalities in the urban areas. Consequently, a ward is under the municipality and the municipality is under the metropolis. There is no specific number of wards and villages. Figure 1 demonstrates the overall administrative geography of the government of Bangladesh.
The administrative geography of the Government of Bangladesh. Adopted from: Bangladesh National Portal [
The World Bank [6] reported that approximately 162 million people are living in this country. The World Bank [6] also claimed that in 2016, there are nearly 1253 people per sq. km. However, nearly 35% of the total population are living in urban areas for their employment.
The economic status of the citizens is improving, but still, possibly 25% of the total population are living under the poverty line [7]. In the year 2016, the growth domestic product (GDP) per capita was 1358.78 US$, and in the same year, the annual growth rate was 7.11 US$ [6].
According to Muhammad et al. [8], the healthcare system of Bangladesh has achieved the Millennium Development Goal Four (MDG-4) by reducing infant mortality rate and growth rate, and maternal and child health improvement. Consequently, life expectancy at birth has increased. As an example, the World Bank [9] reported that in 2005, the life expectancy at birth was 67.94 years and in the year 2015, it reached 72.22 years (i.e. male 70.59 years and female 73.94 years). It is comparatively higher than other state members in SAARC. As evidence, the Bhutanese life expectancy was 69.8 years; Indian was 68.3 years, and Myanmar was 66.3 years in the year 2015 data. However, Ahmed et al. [10] claimed that the health system of Bangladesh had achieved MDG-4 and better life expectancy, though several life-threatening diseases still remain.
The top five causes of death in Bangladesh are heart disease, stroke, Chronic Obstetric Pulmonary Diseases (COPD), lower respiratory infections, and diabetes [11]. The mortality rate of infectious diseases, maternal, prenatal, and nutritional conditions gradually went down from 30.9% in the year 2010 to 25.3% of total death in the year 2015 [12]. Relatively, the mortality rate of non-communicable diseases is now rising and going to be a major health challenge and life-threatening diseases in Bangladesh [8]. NCDs caused almost 67% of the total death [9]. Significantly, stroke caused more than half of the total NCD fatalities in Bangladesh [13]. And due to the shortage of the health workforce and inefficient management, it was difficult to provide proper services for people who had strokes [4]. Table 1 demonstrated all related data by selecting the major geographical, socio-demographic, economic, and health status of the citizens of Bangladesh.
According to the American Stroke Association [15], stroke is one of the NCDs which is a medical emergency characterized by a neurological deficit attributed to an acute focal injury of the central nervous system (CNS) by a vascular cause, including cerebral infarction, intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH) and it is a major cause of disability and death worldwide.
Nearly 4.46 million people have died due to stroke per year; 1.2 million in developed countries and nearly 3.2 million in developing countries [16]. For example, stroke was the 4th leading cause of death for US citizens in the year 2010 [17]. In every 40 seconds, someone was attacked by a stroke, and in every 4 minutes, someone died because of the stroke. It was also the leading cause of long-term disability in the United States. Similarly, in the year 2012 Australia projected that 377,000 people had a stroke sometime in their lives; and in 2013, the estimated deaths due to stroke were 8100 people [18]. Additionally, the stroke prevalence in European countries was also more similar to that in other countries. In 2015, it was found that, in the Netherlands, 0.2% of the total population had suffered from stroke each year [19]. Moreover, in 2008, around 3.7 million Southeast Asian people died from stroke. Islam et al. [20] reported that in Bangladesh, approximately 48,951 people had died due to stroke.
According to mortality, morbidity, and long-term disability rate, stroke is the second leading NCD in Bangladesh [11]. Nearly 113.9 persons per 100,000 had died due to stroke in the year 2013, and the increasing rate per year was 4.9% [21]. A total of 20% stroke patients died immediately in the acute phase, and 80% of the stroke survivors lived with minor or major disabilities [22]. Moreover, Centre for Injury Prevention Health Development and Research Bangladesh (CIPRB) [23] reported that approximately 15 out of 1000 Bangladeshi people were affected by stroke. Additionally, Islam et al. [20] found that the prevalence of stroke is 0.03% and it is snowballing. Nearly 485 out of 10,000 people died suffering from stroke disability [20]. Mamin et al. [24] found that nearly 82.5% Bangladeshi stroke survivors’ age ranged between 41 and 60 years. Consequently, the big proportions of working people have lost their functional ability and it greatly impacts the economy of Bangladesh.
The American Stroke Association [25] claimed that the stroke effects depend on the lesion of the area of the brain cell. Different areas of the brain cell are responsible for different activities. Due to the lesion of the brain cell, the stroke effects can be physical paralysis, memory loss, speech loss, emotional, and behavioral problems. Wolfe [26] claimed that the stroke impacts could be explained from the perspectives of the government, society, family, and patient. From there, the socio-economic impact of stroke is more common in developing countries. Similarly, Institute for Health Metrics and Evaluation [11] reported that a stroke is a great economic burden for a developing country like Bangladesh.
According to Mamin et al. [24], nearly 77% of stroke survivors were public or private or self-employed in Bangladesh. Similarly, Global Health Statistics [21] reported that a big proportion of the working-age group and healthy life had been lost due to stroke in Bangladesh. For example, an estimated 1259.1 people at the age range of 30–34, 9102.9 people at the age range of 50–54, and 21695.5 people at the age range of 60–64 were affected by stroke and lost their functional life in the year 2014. Therefore, the government of Bangladesh has lost a big proportion of its workforce, and it greatly impacts the government and the economy.
Besides, Mohammad [22] claimed that the physical limitation of the patients greatly impacted the patients’ participation in the social programs or activities in society. They need long-term hospitalization and rehabilitation services, and the family has to look after them. However, Disability in Bangladesh (2004) reported that it is difficult to bear the whole treatment cost and the health system of Bangladesh has no health insurance package for their citizens. Therefore, it is also an economic burden for their families [11]. According to Mohammad [22], the burden of stroke is not only for their families, but it is also a burden for the patient because of their post-stroke disabilities and impairments.
The post-stroke means a group of conditions including physical disability, emotional disturbance, and loss of cognition [27]. At the post-stroke phase, patients suffered from several complications; such as pressure sores, urinary tract infections (UTI), joint contraction, aspiration pneumonia, and recurrent stroke due to lack of proper healthcare services [2]. Consequently, these complications could be a leading reason for readmission and also for excruciating death. Gordon et al. [28] reported that daily activity or daily routine exercise helps the post-stroke patients’ to reduce immobility and make them as functional as possible. Therefore, the post-stroke phase is more crucial. Additionally, Runa [29] found that post-stroke complication is a very common problem in Bangladesh.
Accordingly, Mohammad [22] claimed that better care and rehabilitation services could get them back to their independent life. The better quality of healthcare services means a better patient experience, and it is associated with better health outcomes with a higher level of loyalty to follow preventive and treatment strategies of the hospital personnel [30]. Therefore, the healthcare system needs to ensure better and sustainable healthcare services to reduce post-stroke patients’ complications by increasing the better patient experience and patient participation in healthcare [31].
The health system is a dynamic and enduring obligation to peoples’ health throughout their lifespan [32]. The primary purpose of the health system is to provide healthcare services to promote, restore or maintain the health of the nation [33]. According to the healthcare policy and
All the national specialized and medical college hospitals are providing the tertiary level of healthcare services [10]. According to the Ministry of Health and Family Welfare [4], there are numerous condition-based specialized hospitals and 14 medical college hospitals that provide the tertiary level of healthcare services, and these are the highest level of referral hospitals in the health system of Bangladesh. Ahmad [36] reported that this tertiary care concentrated more on curative and intensive healthcare services along with rehabilitative care services and ignored the promotive and preventive care services. Besides, Mamin et al. [24] claimed that the public hospitals also wanted to avoid these rehabilitation services in the health systems of Bangladesh.
In regard to stroke care, all public and private hospitals are serving their in-patient intensive curative care and treatment services [4]. However, only a few of them are providing after-stroke rehabilitation services at the physical rehabilitation department on an out-patient basis [37]. Separately, the non-profit organization as the Centre for the Rehabilitation of the Paralyzed (CRP) is providing after-stroke rehabilitation services in both ways (i.e. in-patient and out-patient basis) [38]. The CRP also extended its branches and services across the six divisions in the health systems of Bangladesh [39].
According to the Ministry of Health and Family Welfare [4], secondary care or less intensive care is being provided at the district general hospitals. There are 62 district general hospitals to serve their secondary care services throughout the districts of the country. Secondary care includes curative, promotive, and preventive services. The promotive and preventive care services are being provided only for infectious diseases (i.e. Tuberculosis, Malaria, influenza, etc.) [40]. These secondary care hospitals are the first referral hospital in the health system of Bangladesh, and it does not provide rehabilitation services.
According to the Ministry of Health and Family Welfare [4], primary care includes curative, promotive, and preventive treatment facilities along with rehabilitative services. The primary care services are being provided at the sub-district or Upazila level, union level, and community level. At this primary care level, the public sector provided the services free of charge. The Upazila health complex and Union sub-centers are committed to providing curative, promotive, and preventive services only. There are 491 Upazila health complex hospitals and 3134 Union Sub-centers at the primary care level to provide in-patient and out-patient services. There are 13,336 community clinics serving maternal and child-related outdoor primary care services with basic medicines. Besides, Biswas et al. [40] reported that the Upazila health complex with the cooperation of NGOs has been running an NCD corner (i.e. fast-track corner) at the primary care level of Bangladesh to prevent the risk factors of NCDs. Consequently, due to the lack of healthcare personnel of the public sector, the NGOs are providing community-based rehabilitation services at this primary care level free of charge.
Table 2 lists all the hospitals and other healthcare facilities beneath the Directorate General of Health Services (DGHS) of the Ministry of Health and Family Welfare of Bangladesh. There is no list of private hospitals; thus, only public hospitals’ information is listed in the table. In this table, the type of hospital services includes inpatient and outpatient types of services.
Subject | Indicators | Value |
---|---|---|
Area | Total land area (sq. km) | 147,570 |
Population | Total population in the year 2016 (in million) Density in 2016 (per sq. km) Crude birth rate in 2015 (per 1000) Crude death rate in 2015 (per 1000) | 162 1251.84 19.23 5.31 |
Life-expectancy | Male in the year 2016 (at birth) Female in the year 2016 (at birth) Total in the year 2016 (at birth) | 70.59 73.94 72.22 |
Economic condition | GDP per capita in 2016 (US $) GDP per capita PPP in 2016 (US $) Annual Growth rate in 2016 | 1358.78 3580.70 7.11 |
Ethnicity | Muslim (% of total population) Hinduism (% of total population) Others (% of total population) | 90 9 1 |
Communicable diseases | Total mortality rate in 2015 (% of total death) | 25.3 |
Non-communicable diseases | Total mortality rate in 2015 (% of total death) | 66.9 |
Level of facilities | Type of facilities | Type of services | Total no. of facilities | Bed occupancy |
---|---|---|---|---|
Secondary & Tertiary level hospitals and other facilities under DGHS | ||||
District | 50-bed hospital District & General hospital | Hospital Hospital | 2 65 | 100 10,328 |
Divisional & National level | Chest diseases hospital Dental college hospital Hospital for alternative medicine Infectious disease hospital Leprosy hospital Medical college hospital Other hospitals Specialized hospital Specialty post-graduate institute and hospital Trauma centre Chittagong skin & hygiene treatment centre National asthma centre National centre for control of rheumatoid fever and heart diseases | Hospital Hospital Hospital Hospital Hospital Hospital Hospital Hospital Hospital Hospital Hospital Hospital Hospital | 13 1 2 5 3 14 4 3 11 5 1 1 1 | 866 200 200 180 130 12,963 325 850 3184 100 N/A N/A N/A |
Total number of hospitals and other facilities | 131 | 29,426 | ||
Primary level healthcare facilities | ||||
Upazila | Upazila health complex (50 bed) Upazila health complex (31 bed) Upazila health complex (10 bed) Upazila health complex (0 bed) Upazila health office 31-bed hospital 30-bed hospital | Hospital Hospital Hospital Hospital Outdoor Hospital Hospital | 297 113 11 3 60 5 2 | 14,850 3503 110 0 …… 155 60 |
Total Upazila level facilities | 491 | 18,678 | ||
Union | 20-bed hospital 10-bed hospital Union sub-center Union health and family welfare center | Hospital Hospital Outdoor Outdoor | 32 19 1498 1585 | 640 190 …… …… |
Total union level facilities | 3134 | 830 | ||
Word | Community clinic (at present) | Outdoor | 13,336 | …… |
Grand total primary level hospitals | 482 | 19,508 | ||
Grand total primary level facilities | 16,968 | 19,508 | ||
Grand total health facilities under DGHS of Bangladesh | 17,099 | 48,934 |
The hospitals and other healthcare facilities under the DGHS of Bangladesh.
Source: Ministry of Health and Family Welfare [4].
The Ministry of Health and Family Welfare [41] reported that there were 74,099 physicians, 6,481 dental surgeons, almost 46,000 registered nurses, 775 pharmacists, 6,029 medical technologists, and 66,623 community health workers. The number of physicians and population ratio was 4.5 per 10,000 populations. There was no more data on the rehabilitation professionals, only a little information available about the physical therapist. The Ministry of Health and Family Welfare [4] reported that in the public sector, nearly 117 physiotherapists are working. Separately, World Confederation for Physical Therapy (WCPT) [42] reported that approximately 1,600 physiotherapists are working in the whole Bangladesh healthcare service sectors. According to a 2016 report of the Bangladesh Health Professionals Institute (BHPI), 241 occupational therapists have graduated and are working in various national and international organizations and hospitals in the country and abroad [43]. The Society of Speech and Language Therapists (SSLTs) reports that speech and language therapy is a relatively new profession in comparing with other rehabilitation professions in Bangladesh and as of 2016, there are 104 graduate speech and language therapists those are working in various national and international healthcare organizations in Bangladesh [44]. Approximately, 25 to 30 students from each department of BHPI (the academic institute of CRP) (Occupational Therapy and Speech and Language Therapy) completing their graduate program each year and initiate clinical practices [39]. Table 3 demonstrated the healthcare personnel and population ratio of serving healthcare services healthcare services in Bangladesh. Therefore, the availability of rehabilitation services and the fee for the services are the greatest challenge for the person with rehabilitation service needs.
Healthcare providers and population ratio | ||
---|---|---|
Healthcare personnel | Number | Ratio |
Physician | 74,099 | 4.5: 10,000 people |
Neurologist | 60 | 0.004: 10,000 people |
Dental surgeons | 6481 | 0.40: 10,000 people |
Registered nurse | 46,000 | 2.84: 10,000 people |
Physical therapist | 1600 | 0.1: 10,000 people |
Occupational Therapist | 241 | 0.024: 10,000 people |
Speech and Language Therapist | 104 | 0.010: 10,000 People |
Community health worker | 66,623 | 4.11: 10,000 people |
According to Bangladesh National Health Accounts [45], the total health expenditure was only 3.5% of the total GDP. It is relatively low, and according to per capita, the health expenditure was 27 US$. However, from this expenditure, the government invested only 23%, and the rest of the amount came from out-of-pocket payments. According to Ahmed et al. [10], this out-of-pocket payment was almost 63% of total healthcare cost. Besides, there was no specific budget for stroke and post-stroke patients and their healthcare services. Moreover, the Ministry of Health and Family Welfare [4] reported that they invested only 2714 million BDT taka (32 million US$) for overall NCDs surveillance. This was a very small expenditure compared to the expenditures on communicable and maternal diseases (i.e. 579 million US$) in the healthcare service system of Bangladesh. Therefore, financial challenge is a big challenge to provide NCD-related healthcare programs in the healthcare system of Bangladesh.
Since the liberation, the health system of Bangladesh has been concentrating on controlling communicable and maternal and child-related diseases [10]. Global Health Statistics [21] reported that within the last decade the burden of NCDs is snowballing and has become a major health challenge for Bangladeshi citizens. Furthermore, the Ministry of Health and Family Welfare concentrated on this issue, and with the cooperation of NGOs and private organizations, they developed different policies and had been implementing these to strengthen the healthcare system of Bangladesh [40].
There is no specific policy and program for after-stroke disability. All the policies are focused on preventive and promotive health care services to control the risk factors of NCDs including stroke. However, these services are also important to reduce the second episode of stroke attack [46] such as the Health, Nutrition and Population Strategic Investment Plan (HNPSI) for six years (2016–2021) to inter-organization collaborative work and improve healthy lifestyles [4];
The health system of Bangladesh has been following a pluralistic healthcare system. The Ministry of Health and Family Welfare is the main government organization of the health system of Bangladesh [4]. This ministry is responsible for providing curative, promotive, and preventive services through tertiary care, secondary care, and primary care organizations. For rehabilitation services, the Ministry of Social Welfare is the responsible government organization, but at present both ministries (i.e. Ministry of Health and Family Welfare and Ministry of Social Welfare) are working collaboratively to serve rehabilitation services at the different levels of healthcare services [47].
The public sector in the health systems of Bangladesh did not concentrate more on rehabilitation services [24]. Thus, the private sectors (for-profit organizations) and NGOs (not-for-profit organizations) extended their healthcare services including rehabilitation services [20]. A few of the private hospitals are providing post-stroke rehabilitation services at tertiary care level hospitals on an inpatient and outpatient basis. Along with the private sectors, several NGOs under the Ministry of Social Welfare have been offering post-stroke rehabilitation services within the community and hospital [40]. These NGOs are the Bangladesh Rehabilitation Assistance Committee (BRAC), Handicap International (HI), International Committee of the Red Cross (ICRC), and the CRP (Handicap International (HI) [48] and Islam et al. [20]). The International Committee of the Red Cross (ICRC) with the collaboration of CRP has been providing rehabilitation services in the community [49]. While only the CRP provides hospital-based stroke rehabilitation services besides community-based rehabilitation services.
The CRP is offering rehabilitation services throughout the six divisions of the administrative geography of Bangladesh [39]. The CRP is also committed to provide Multi-Disciplinary Team (MDT) based rehabilitation services. According to Gresham et al. [50], the rehabilitation services by a multidisciplinary team provide better health outcomes after-stroke disabilities. The MDT approach consists of different specialists or professionals, those working in a team according to the needs of the patient [51]. In this approach, all professionals are offering their highest potential skills to change the patients’ condition as much as possible. Figure 2 demonstrates the overall service structures of the Bangladesh healthcare system.
Health service systems structure in Bangladesh health systems. Adopted from:
According to CRP [39], the CRP is a not-for-profit NGO to serve rehabilitation services for person with disabilities. CRP’s vision is “to ensure the inclusion of girls and boys, women and men with disabilities into mainstream society.” To achieve this vision, CRP worked with several missions such as “to promote an environment where all girls and boys, women and men with disabilities have equal access to health, rehabilitation, education, employment, the physical environment, and information.” The CRP is coordinated by a committee, and it is committed to serving quality services.
Trust for Rehabilitation of the Paralyzed (TRP) is the central committee and all the decisions such as policy, programs, and implementation are being addressed by the recommendation of this committee. The executive director coordinates all the CRP services throughout the CRP branches. The program manager helps the executive director to coordinate all the programs. The program manager divides all the CRP activities into various programs or services. Every wing is being coordinated by the head of the wing along with several heads of the departments. Additionally, there is the academic wing to provide the skillful rehabilitation professionals to serve the quality services toward the patients. It has ten branches, and the medical service wing is responsible for serving all healthcare services.
In this context, the physical therapy department is responsible for recovering physical functions, the occupational therapy department for recovering daily activities, and the speech and language therapy department for recovering communication and swallowing difficulties. According to CRP policy, all medical professionals have to wear hospital uniform during therapy services. Only the five CRP divisional hospital branches (i.e. Rajshahi, Chittagong, Barisal, Sylhet- Moulvibazar, and Mymensingh branches) along with the main branch of Dhaka division has been providing the out-patient medical services and rehabilitation services. The rest of the branches are responsible for providing Community-Based Rehabilitation (CBR) services and health promotion and prevention activities beneath the rehabilitation wing. CBR is offering these services five full days a week, from 8 am to 5 pm. There are several departments, and the research and evaluation department coordinates all the research-oriented formalities in the CRP. CBR collects donation and undergoes several income-generating activities to enhance the endowment to run the healthcare services (i.e. CRP cafeteria, nursery, woodshop, etc.). Figure 3 demonstrates the CRP management organogram with several services and activities throughout the country.
The organogram of the CRP activities in Bangladesh. Sources: Adapted from [
The CRP (2016) reported that all of 755 dedicated employees are working throughout this organization and its branches. However, there is no exact data for the total number of separate rehabilitation professionals.
The rehabilitation service systems and stroke care depend on the severity of the patients and the episodes of the stroke attack [52]. They have mentioned two phases; the acute phase and the sub-acute phase of stroke care. However, Pitthayapong et al. [2] added the post-stroke phase and it is started at the end of the acute and subacute periods of stroke.
Acute stroke care means care that takes place 24–48 hours after stroke, and during this period they need more intensive comprehensive services including rehabilitation if possible [52]. Particularly, inpatient rehabilitation care units of the hospitals serve the acute stroke care services, and the tertiary/specialized hospitals and divisional general hospitals provide comprehensive stroke care services under the healthcare services structure of Bangladesh ([53]; Bhowmik et al. [7]; & Nessa et al. [37]).
At the end of the acute period of stroke, the sub-acute period of stroke starts, and the duration of this phase is one week until one month [52]. At this period the neurological condition of the stroke patients is more stabilized than during the acute stroke period, and from this phase, they attend a regular rehabilitation program [54]. The acute and sub-acute stroke patient services are similarly available in the tertiary/specialized hospitals and divisional general hospitals in Bangladesh (Directorate General of Health Services [53]; Bhowmik et al. [7]; Nessa et al. [37]).
Post-stroke care is care that started at the end of the acute and sub-acute phase of stroke patients [55]. However, Habib and Hirschfeld [56] found that the post-stroke care with the integration of rehabilitation services was effective. The limited specialized public and private hospitals at the tertiary level and the CRP hospital provide after-stroke/post-stroke rehabilitation services. The NGOs and Upazila health complex hospitals provide preventive and promotive services for reducing the risk factors of the second episode of stroke attack in the health systems of Bangladesh (Biswas et al. [40] & Ahmed et al. [10]).
The stroke care pathways in the Bangladesh health service system are complex and difficult to control. According to Biswas et al. [40], first, the patient visits the Upazila health complex, and if the responsible health professional notices any signs and symptoms of the stroke risk factors, then they suggest that the patient has to continue the preventive and promotive services from the NCDs corner. Directorate General of Health Services [53] reported that according to the stroke management guideline; if the patient needs emergency services, they are referred to the district hospital for secondary care. Thus, the district hospital takes care of this patient according to their available resources. If the patient’s condition becomes more severe, then the district hospital refers the patient to the tertiary or specialized hospitals for more intensive care and neurological treatment.
According to this stroke management guideline, after completing the acute stage, some of the hospitals send them to the rehabilitation hospital or the rehabilitation unit of the hospitals for early rehabilitation services [53]. Moreover, the rehabilitation professionals are working with those post-stroke patients with a set of standard goals, and after achieving this goal, they send them back to the community or home to continue community-based rehabilitation services by several NGOs [10, 20, 39]. Similarly, they are continuing preventive and promotive services through NCDs corner of the primary care level to reduce the second chance of stroke attack [40]. This study concentrated only on the post-stroke out-patient rehabilitation services system in Bangladesh. According to Ahmed et al. [10], CRP is a rehabilitation center for serving post-stroke rehabilitation services in Bangladesh. It is serving hospital-based inpatient, out-patient, domiciliary, and community-based rehabilitation services. Figure 4 shows the stroke and post-stroke care pathways along with the rehabilitation services in Bangladesh.
Stroke and post-stroke care pathways along with the rehabilitation services in Bangladesh. Adopted from: Directorate General of Health Services [
According to Runa [29], CRP is the biggest rehabilitation hospital in Bangladesh. It provides comprehensive post-stroke rehabilitation services following a Multi-Disciplinary Team (MDT) approach. The MDT team is composed of a physician, physiotherapist, occupational therapist, speech and language therapist, rehabilitation nurse, and patient’s caregiver.
According to the CRP service delivery process [39], at the first contact, the patient comes to the reception (1) to collect the serial token, and after collecting the token, they have to wait in the waiting areas (2) for MDT screening (3). The MDT professionals screen the patient’s condition and consequently recommend the patient for further rehabilitation services. According to the MDT recommendations, the patient goes to the laboratory (4) for the clinical test if recommended and reception (5) for the appointment of outpatient rehabilitation services. There are three departments; physical therapy, occupational therapy, and speech and language therapy for post-stroke rehabilitation services. After collecting the therapists’ appointment from the reception, the patient has to go to the recommended departments (6) to receive the therapy services and wait for therapy timing (7). However, the patient may have to visit several departments based on the patient’s needs. The repetition of the therapy session depends on the patients’ physical stability and availability of the therapy session. The three departments professional demonstrate a health education program (8) at the end of their therapy session. The main purpose of this program is to provide knowledge about stroke risk factors prevention and health promotional activities.
At the end of the session, according to the therapist’s recommendation, the patient may have to go to the pharmacy (9) and the reception (10) again for further appointments. Finally, the patient goes back home (11, 12) and comes again on another day for a laboratory report and the next appointments if needed. Otherwise, the patient and the patient’s caregiver can get help from CRP telemedicine services (13) and CBR services. Using this telecommunications service, they can continue their therapy services at home (Figure 5) [39].
Demonstrated the overall post-stroke outpatient rehabilitation services pathways in the CRP hospital. Sources and Adopted: From, CRP [
The Republic of India is a border country of Bangladesh. India is surrounded almost entirely by sharing its’ borders within west, north, and east areas. It has been following a three-tiered model of health care service delivery. These tiered models comprise of primary, secondary, and tertiary level of healthcare services. The primary healthcare centers are particularly focusing on prevention, recognition, and referral for rehabilitation. The secondary level at district hospitals has fortified with medical doctors and other general facilities. At the divisional level, all tertiary care hospitals have equipped with all specialized facilities that are provided by public and private healthcare organizations [57]. There are enormous differences in accessibility and affordability in private and public hospitals for post-stroke healthcare services. For this circumstance, it’s becoming a major challenge for the patients who are seeking quality healthcare facilities for after-stroke patients.
The Republic of the Union of Myanmar has been sharing its border with the country of Bangladesh. Myanmar has been following pluralistic healthcare system followed by public, private, and NGO sectors. Ministry of Health (MOH) and other professional organizations have been working collaboratively for reducing communicable diseases. While communicable diseases declined, non-communicable diseases have been rising as a major concerning issue in Myanmar. The Department of Health (DOH) is mainly responsible for ensuring healthcare services through rural health centres (RHCs) and sub-rural health centres (Sub-RHCs) in the corresponding the municipality, district, and regional health centers. Preventive, promotive, and rehabilitative services have been providing for all citizens as well as for post-stroke patients to reduce premature deaths. All RHCs, Sub-RHCs are providing primary care services and at the regional level has available emergency and specialized hospital services based on the patients’ need [58].
Nepal is a state of government that has spanned a decade of political disturbance, revolution, and ferocity from the years 1996 to 2006. That particularly affects the development of healthcare sectors in Nepal. In this regard, private sectors have been following a leading role in ensuring healthcare services for the citizens of Nepal. Nepal’s healthcare system is struggling to control infectious diseases and the Ministry of Health and Population (MoHP) has made a significant achievement in reducing infectious diseases. However, due to demographic changes and urbanization, the burden of national diseases has shifted from infectious to non-infectious disease patterns [59]. Wherein, 108 out of every 100,000 deaths in Nepal are occurring by cerebrovascular diseases and almost 543/100,000 persons have led a Disability-Adjusted Life Years (DALY) after their stroke [60]. Public and private sectors have been providing curative and rehabilitative services but, patients have to depend on the private sector for emergency and specialized hospital facilities. The affordability of medical treatment has considered a major role in accessing hospital facilities for all citizens. Besides, out-of-pocket payment is a very common problem in Nepal to receive in-patients hospital services.
The Royal Government of Bhutan provides free health care services by following the principles of primary healthcare strategy. Bhutan has improved slowly on the way to building a strong health system. However, the Ministry of Health (MoH) has faced several burdens of diseases where the prevalence of non-communicable diseases (NCDs) is aggravated. To fight against the growing trend of NCDs, Bhutan has applied a multisectoral national action plan to prevent health risks of NCDs [61].
The Maldives is a developing country where the government is the head of the country. The Maldives has achieved a distinguished improvement in the health status of all citizens in gaining five out of eight Millennium Development Goals (MDGs) that creates a strong basement in achieving sustainable development goals (SDGs). However, considering the socioeconomic and environmental changes, the country has faced new challenges in controlling non-communicable diseases (NCDs). About 81% of total deaths are caused by NCDs in the Maldives. To address the burden of NCDs, a multisectoral national plan of action has been developed and implemented in focusing on preventive and promotional health interventions to bring changes in lifestyles and reduce health risks of NCDs. The Ministry of Health (MoH) is primarily responsible for ensuring primary health care facilities for all citizens, where, some private hospitals and NGOs provide healthcare in collaboration with the public sector. The government has spent the maximum amount of the total budget in the health sector. For instance, out-of-pocket payments for healthcare services are declining [59, 62].
The burden of NCDs as well as stroke is not an issue of a particular country. Globally, it is now a common public health concerning issue. World Health Organization has been working worldwide in dropping down the risk of NCDs. Several countries have adopted a multisectoral collaboration approach to improve health status and work collaboratively with the participation of all individuals in different sectors. In Bangladesh, the Ministry of Health and Family Welfare in cooperation with various NGOs and private organizations has launched NCD corner at the Upazila level for providing preventive, promotional, and rehabilitative services in the community for persons who are having health risks and after-stroke disability. The scarcity of healthcare personnel is also an important barrier for providing such services. At the same time, healthcare financing and lack of infrastructure are the most important hindering factors for maintaining these kinds of services in the community. Therefore, this is the time for the ministry of health and family welfare to work with other ministries and donor agencies for the betterment of all citizens of Bangladesh.
In order to reduce the bureaucratic problem in adopting any approach related to healthcare in society, the government has to implement a decentralization system.
The government should increase the annual health care budget for providing low-cost or free treatment facilities. In this case, the government should work with various national and international donor agencies for financial assistance.
Government and other legislative organizations need to work on primary care practices in both rural and urban areas by increasing the capacity of primary care workers. Similarly, it recommends considering planning environmental changes to make the infrastructure user-friendly and accessible to all.
Local community leaders, social workers, and general people are needed to be aware of the health risk of NCDs. In this case, a multisectoral collaboration in action approach would be an effective way to work collaboratively as well as initiating telerehabilitation services, remote rehabilitation services, public education, and awareness for early rehabilitation in reducing health risks of affecting NDCs.
Continuous quality control and monitoring systems are needed for maintaining the quality of the healthcare services as well as strengthening the healthcare service systems of Bangladesh.
The study authors declared that there is no conflict of interest.
Bangladesh Rehabilitation Assistance Committee
Community-Based Rehabilitation
Central Nervous System
Chronic Obstetric Pulmonary Diseases
Centre for Rehabilitation of the Paralyzed
Disability-Adjusted Life Year
Directorate General of Health Services
Department of Health
Growth Domestic Product
Handicap International
Health, Nutrition and Population Strategic Investment
Intracerebral Hemorrhage
International Committee of the Red Cross
Millennium Development Goal
Multi-Disciplinary Team
Ministry of Health
Ministry of Health and Family Welfare
Ministry of Health and Population
Non-Communicable Diseases
Rural Health Centre
South Asian Association of Regional Cooperation
Subarachnoid Hemorrhage
Sustainable Development Goals
South-East Asia Region
Society of Speech and Language Therapists
Trust for Rehabilitation of the Paralyzed
Urinary Tract Infections
World Confederation for Physical Therapy
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This chapter provides an overview of the time series methods that can be used for more accurate wind and solar forecasting.",book:{id:"6138",slug:"time-series-analysis-and-applications",title:"Time Series Analysis and Applications",fullTitle:"Time Series Analysis and Applications"},signatures:"Mahmoud Ghofrani and Musaad Alolayan",authors:[{id:"183482",title:"Dr.",name:"Mahmoud",middleName:null,surname:"Ghofrani",slug:"mahmoud-ghofrani",fullName:"Mahmoud Ghofrani"},{id:"217089",title:"Mr.",name:"Musaad",middleName:null,surname:"Alolayan",slug:"musaad-alolayan",fullName:"Musaad Alolayan"}]},{id:"71673",doi:"10.5772/intechopen.91935",title:"Data Processing Using Artificial Neural Networks",slug:"data-processing-using-artificial-neural-networks",totalDownloads:1539,totalCrossrefCites:5,totalDimensionsCites:13,abstract:"The artificial neural network (ANN) is a machine learning (ML) methodology that evolved and developed from the scheme of imitating the human brain. 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All the topics have been discussed in such a scheme to give the reader the basic concept and clarity in a sequential way from ANN perceptron model to deep learning models and underlying types.",book:{id:"9966",slug:"dynamic-data-assimilation-beating-the-uncertainties",title:"Dynamic Data Assimilation",fullTitle:"Dynamic Data Assimilation - Beating the Uncertainties"},signatures:"Wesam Salah Alaloul and Abdul Hannan Qureshi",authors:[{id:"316063",title:"Dr.",name:"Wesam Salah",middleName:null,surname:"Alaloul",slug:"wesam-salah-alaloul",fullName:"Wesam Salah Alaloul"}]},{id:"57016",doi:"10.5772/intechopen.70826",title:"Symbolic Time Series Analysis and Its Application in Social Sciences",slug:"symbolic-time-series-analysis-and-its-application-in-social-sciences",totalDownloads:1239,totalCrossrefCites:2,totalDimensionsCites:7,abstract:"The present chapter intents to present the symbolic time series analysis (STSA) reviewing the recent developments in sciences. Even if there are very few works applied to social sciences, STSA has a potential to be developed. In particular, due to the limitations about historical data, fields such as Economics and Finance need to develop statistical tests to prove their hypotheses. An independence test and a causality test based on STSA are reviewed. They seem to be more powerful, detecting different kinds of nonlinearities compared with the classical tests, usually applied in social sciences. However, there is much work to do with STSA, and social sciences are a fertile field for the development of new powerful tools.",book:{id:"6138",slug:"time-series-analysis-and-applications",title:"Time Series Analysis and Applications",fullTitle:"Time Series Analysis and Applications"},signatures:"Wiston Adrián Risso",authors:[{id:"209909",title:"Dr.",name:"Wiston",middleName:null,surname:"Risso",slug:"wiston-risso",fullName:"Wiston Risso"}]},{id:"60170",doi:"10.5772/intechopen.74854",title:"Multivariate Adaptive Regression Splines in Standard Cell Characterization for Nanometer Technology in Semiconductor",slug:"multivariate-adaptive-regression-splines-in-standard-cell-characterization-for-nanometer-technology-",totalDownloads:985,totalCrossrefCites:1,totalDimensionsCites:4,abstract:"Multivariate adaptive regression splines (MARSP) is a nonparametric regression method. It is an adaptive procedure which does not have any predetermined regression model. With that said, the model structure of MARSP is constructed dynamically and adaptively according to the information derived from the data. Because of its ability to capture essential nonlinearities and interactions, MARSP is considered as a great fit for high-dimension problems. This chapter gives an application of MARSP in semiconductor field, more specifically, in standard cell characterization. The objective of standard cell characterization is to create a set of high-quality models of a standard cell library that accurately and efficiently capture cell behaviors. In this chapter, the MARSP method is employed to characterize the gate delay as a function of many parameters including process-voltage-temperature parameters. Due to its ability of capturing essential nonlinearities and interactions, MARSP method helps to achieve significant accuracy improvement.",book:{id:"6230",slug:"topics-in-splines-and-applications",title:"Topics in Splines and Applications",fullTitle:"Topics in Splines and Applications"},signatures:"Taizhi Liu",authors:[{id:"209988",title:"Dr.",name:"Taizhi",middleName:null,surname:"Liu",slug:"taizhi-liu",fullName:"Taizhi Liu"}]},{id:"73445",doi:"10.5772/intechopen.92863",title:"Estimation for Motion in Tracking and Detection Objects with Kalman Filter",slug:"estimation-for-motion-in-tracking-and-detection-objects-with-kalman-filter",totalDownloads:569,totalCrossrefCites:2,totalDimensionsCites:4,abstract:"The Kalman filter has long been regarded as the optimal solution to many applications in computer vision for example the tracking objects, prediction and correction tasks. Its use in the analysis of visual motion has been documented frequently, we can use in computer vision and open cv in different applications in reality for example robotics, military image and video, medical applications, security in public and privacy society, etc. In this paper, we investigate the implementation of a Matlab code for a Kalman Filter using three algorithm for tracking and detection objects in video sequences (block-matching (Motion Estimation) and Camshift Meanshift (localization, detection and tracking object)). The Kalman filter is presented in three steps: prediction, estimation (correction) and update. The first step is a prediction for the parameters of the tracking and detection objects. The second step is a correction and estimation of the prediction parameters. The important application in Kalman filter is the localization and tracking mono-objects and multi-objects are given in results. This works presents the extension of an integrated modeling and simulation tool for the tracking and detection objects in computer vision described at different models of algorithms in implementation systems.",book:{id:"9966",slug:"dynamic-data-assimilation-beating-the-uncertainties",title:"Dynamic Data Assimilation",fullTitle:"Dynamic Data Assimilation - Beating the Uncertainties"},signatures:"Afef Salhi, Fahmi Ghozzi and Ahmed Fakhfakh",authors:[{id:"315126",title:"Dr.",name:"Afef",middleName:null,surname:"Salhi",slug:"afef-salhi",fullName:"Afef Salhi"},{id:"330600",title:"Dr.",name:"Ahmed",middleName:null,surname:"Fakhfakh",slug:"ahmed-fakhfakh",fullName:"Ahmed Fakhfakh"},{id:"330601",title:"Dr.",name:"Fahmi",middleName:null,surname:"Ghozzi",slug:"fahmi-ghozzi",fullName:"Fahmi Ghozzi"}]}],mostDownloadedChaptersLast30Days:[{id:"71673",title:"Data Processing Using Artificial Neural Networks",slug:"data-processing-using-artificial-neural-networks",totalDownloads:1542,totalCrossrefCites:5,totalDimensionsCites:14,abstract:"The artificial neural network (ANN) is a machine learning (ML) methodology that evolved and developed from the scheme of imitating the human brain. Artificial intelligence (AI) pyramid illustrates the evolution of ML approach to ANN and leading to deep learning (DL). Nowadays, researchers are very much attracted to DL processes due to its ability to overcome the selectivity-invariance problem. In this chapter, ANN has been explained by discussing the network topology and development parameters (number of nodes, number of hidden layers, learning rules and activated function). The basic concept of node and neutron has been explained, with the help of diagrams, leading to the ANN model and its operation. All the topics have been discussed in such a scheme to give the reader the basic concept and clarity in a sequential way from ANN perceptron model to deep learning models and underlying types.",book:{id:"9966",slug:"dynamic-data-assimilation-beating-the-uncertainties",title:"Dynamic Data Assimilation",fullTitle:"Dynamic Data Assimilation - Beating the Uncertainties"},signatures:"Wesam Salah Alaloul and Abdul Hannan Qureshi",authors:[{id:"316063",title:"Dr.",name:"Wesam Salah",middleName:null,surname:"Alaloul",slug:"wesam-salah-alaloul",fullName:"Wesam Salah Alaloul"}]},{id:"72663",title:"The Monte Carlo Techniques and the Complex Probability Paradigm",slug:"the-monte-carlo-techniques-and-the-complex-probability-paradigm",totalDownloads:1958,totalCrossrefCites:2,totalDimensionsCites:2,abstract:"The concept of mathematical probability was established in 1933 by Andrey Nikolaevich Kolmogorov by defining a system of five axioms. This system can be enhanced to encompass the imaginary numbers set after the addition of three novel axioms. As a result, any random experiment can be executed in the complex probabilities set C which is the sum of the real probabilities set R and the imaginary probabilities set M. We aim here to incorporate supplementary imaginary dimensions to the random experiment occurring in the “real” laboratory in R and therefore to compute all the probabilities in the sets R, M, and C. Accordingly, the probability in the whole set C=R+M is constantly equivalent to one independently of the distribution of the input random variable in R, and subsequently the output of the stochastic experiment in R can be determined absolutely in C. This is the consequence of the fact that the probability in C is computed after the subtraction of the chaotic factor from the degree of our knowledge of the nondeterministic experiment. We will apply this innovative paradigm to the well-known Monte Carlo techniques and to their random algorithms and procedures in a novel way.",book:{id:"10062",slug:"forecasting-in-mathematics-recent-advances-new-perspectives-and-applications",title:"Forecasting in Mathematics",fullTitle:"Forecasting in Mathematics - Recent Advances, New Perspectives and Applications"},signatures:"Abdo Abou Jaoude",authors:[{id:"248271",title:"Dr.",name:"Abdo",middleName:null,surname:"Abou Jaoudé",slug:"abdo-abou-jaoude",fullName:"Abdo Abou Jaoudé"}]},{id:"66652",title:"Analysis of Financial Time Series in Frequency Domain Using Neural Networks",slug:"analysis-of-financial-time-series-in-frequency-domain-using-neural-networks",totalDownloads:1574,totalCrossrefCites:2,totalDimensionsCites:2,abstract:"Developing new methods for forecasting of time series and application of existing techniques in different areas represents a permanent concern for both researchers and companies that are interested to gain competitive advantages. Financial market analysis is an important thing for investors who invest money on the market and want some kind of security in multiplying their investment. Between the existing techniques, artificial neural networks have proven to be very good in predicting financial market performance. In this chapter, for time series analysis and forecasting of specific values, nonlinear autoregressive exogenous (NARX) neural network is used. As an input to the network, both data in time domain and those in the frequency domain obtained using the Fourier transform are used. After the experiment was performed, the results were compared to determine the potentially best time series for predicting, as well as the convenience of the domain in which better results are obtained.",book:{id:"7614",slug:"fourier-transforms-century-of-digitalization-and-increasing-expectations",title:"Fourier Transforms",fullTitle:"Fourier Transforms - Century of Digitalization and Increasing Expectations"},signatures:"Stefan Nikolić and Goran Nikolić",authors:[{id:"23261",title:"Prof.",name:"Goran",middleName:"S.",surname:"Nikolic",slug:"goran-nikolic",fullName:"Goran Nikolic"},{id:"280401",title:"B.Sc.",name:"Stefan",middleName:null,surname:"Nikolić",slug:"stefan-nikolic",fullName:"Stefan Nikolić"}]},{id:"79518",title:"Matlab Program Library for Modeling and Simulating Control Systems for Electric Drives Based on Fuzzy Logic",slug:"matlab-program-library-for-modeling-and-simulating-control-systems-for-electric-drives-based-on-fuzz",totalDownloads:362,totalCrossrefCites:0,totalDimensionsCites:1,abstract:"Fuzzy control of the speed of electric drives is an alternative in the field of the control system. Modeling and simulation of electric drive control systems based on fuzzy logic is an important step in design and development. This chapter provides a complete means of modeling and simulation of fuzzy control systems for DC motors, induction motors, and permanent magnet synchronous motors, made in the Matlab/Simulink program environment, useful for performing complex analyzes. The functioning of the programs is demonstrated by an example of characteristics obtained practically, with a functioning regime often encountered in practice.",book:{id:"10402",slug:"matlab-applications-in-engineering",title:"MATLAB Applications in Engineering",fullTitle:"MATLAB Applications in Engineering"},signatures:"Constantin Volosencu",authors:[{id:"1063",title:"Prof.",name:"Constantin",middleName:null,surname:"Volosencu",slug:"constantin-volosencu",fullName:"Constantin Volosencu"}]},{id:"59783",title:"Application of Cubic Spline Interpolation Technique in Power Systems: A Review",slug:"application-of-cubic-spline-interpolation-technique-in-power-systems-a-review",totalDownloads:1463,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"In this chapter, a comprehensive review is made on the application of cubic spline interpolation techniques in the field of power systems. Domains like available transfer capability (ATC), electric arc furnace modeling, static var. compensation, voltage stability margin, and market power determination in deregulated electricity market are taken as samples to illustrate the significance of cubic spline interpolation.",book:{id:"6230",slug:"topics-in-splines-and-applications",title:"Topics in Splines and Applications",fullTitle:"Topics in Splines and Applications"},signatures:"Akhil Prasad, Atul Manmohan, Prabhakar Karthikeyan Shanmugam\nand Kothari D.P.",authors:[{id:"30630",title:"Prof.",name:"Prabhakar",middleName:null,surname:"Karthikeyan Shanmugam",slug:"prabhakar-karthikeyan-shanmugam",fullName:"Prabhakar Karthikeyan Shanmugam"},{id:"209237",title:"Mr.",name:"Akhil",middleName:null,surname:"Prasad",slug:"akhil-prasad",fullName:"Akhil Prasad"},{id:"209238",title:"Mr.",name:"Atul",middleName:null,surname:"Manmohan",slug:"atul-manmohan",fullName:"Atul Manmohan"},{id:"217443",title:"Dr.",name:"Kothari",middleName:null,surname:"D.P",slug:"kothari-d.p",fullName:"Kothari D.P"}]}],onlineFirstChaptersFilter:{topicId:"1407",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:330,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:9,numberOfPublishedChapters:139,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:122,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:112,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:21,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:10,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. 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