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Role of cough syrups and antipyretics in treatment of pediatric cough: Children are not miniature adults

Why do we cough?
Cough is a very elaborate act with the explicit intention of expelling irritants in the respiratory tract The irritants may be intrinsic eg. Mucus & phlegm or extrinsic eg. Foreign particle or body
Cough is reflex-evoked modification of breathing pattern in response to airway irritation

Cough can also be produced voluntarily

How do we cough?
The event of cough is deep inspiration followed by forceful expulsion Diaphragm and external intercostal muscles contract, creating a negative pressure around the lung. Air rushes into the lungs The glottis closes and the vocal cords contract to shut the larynx. The abdominal muscles contract to accentuate the action of the relaxing diaphragm; simultaneously, the other expiratory muscles contract increase the pressure of air within the lungs upto 300mmHg. The vocal cords relax &the glottis opens releasing air at over 100mph. The bronchi and non-cartilaginous portions of the trachea collapse to form slits through which the air is forced, which clears out any irritants attached to the respiratory lining. However mechanical laryngeal stimulation as in aspiration results in immediate expiratory stimulation without the preceding inspiratory phase to protect the airway from aspiration by expiratory reflex.

How do we cough?
Each cough occurs through the stimulation of a complex reflex arc constituted by: Afferent pathway: Sensory nerve fibers located in the ciliated epithelium of the upper airways, branches from the diaphragm. The afferent impulses go to the medulla diffusely. Central Pathway : a central coordinating region for coughing is located in the upper brain stem and pons. Efferent pathway: Impulses from the cough center travel via the vagus, phrenic, and spinal motor nerves to diaphragm, abdominal wall and intercostal muscles.

How do we cough?
This is initiated by the stimulation of cough receptors which are found in the trachea, main carina, branching points of large airways, and more distal smaller airways, the pharynx, external auditory canals, eardrums, paranasal sinuses, pharynx, diaphragm, pleura, pericardium, and stomach. The receptors are mechano-recptors stimulated by irritation by mucus plug, foreign body, particulate matter etc or chemorecptors stimulated by irritants, fumes, aspirates, The afferent neural pathway is through the internal Laryngeal branch of the Superior Laryngeal branch of the Vagus. The efferent neural pathway is mediated through the Vagus, Phrenic nerve & the Intercostal nerves

NOT SMALL ADULTS


(CAUTION WITH EXTRAPOLATING ADULT LITERATURE)

Viruses responsible for common cold in adults may cause serious respiratory illness in kids. Maturational differences in airway anatomy, respiratory musculature, chest wall structure. Differences in medication response. Medical history in young kids is limited by parental perception and availability.
Children should be managed according to the studies and guidelines for children (when available), because etiologic factors and treatments in children are sometimes different from those in adults.

DIAGNOSTIC APPROACHES
Children with chronic cough require careful and systematic evaluation for the presence of specific diagnostic indicators. In children with chronic cough, the etiology should be defined and treatment should be etiologically based.

Children with chronic productive purulent cough should always be investigated to document the presence or absence of bronchiectasis and to identify underlying and treatable causes such as cystic fibrosis and immune deficiency.

History and physical exam first: Specific pointers suggestive of specific cough.

DIAGNOSTIC APPROACHES
Pointers to the Presence of Specific Cough Auscultatory findings, wheeze, crepitations Cardiac abnormalities Chest pain Chest wall deformity Digital clubbing, FTT (CF) Neurodevelopmental (potential for aspiration)
In children with nonspecific cough, cough may spontaneously resolve, but children should be reevaluated for the emergence of specific etiologic pointers.

DIAGNOSTIC APPROACHES

DIAGNOSTIC APPROACHES
12yo male with remote history of URI has been coughing since Thanksgiving.
Children with chronic cough should undergo, as a minimum, CXR and spirometry, if age appropriate.

CXR quick, readily attainable. Spirometry reliably performed in kids > 6 yrs (often >3 yrs, with appropriate personnel).

DIAGNOSTIC APPROACHES
Also considered:
Chest or sinus CT a.) HRCT as current gold standard for eval of small airway anatomy. b.) Lifetime cancer risk is age and dose dependent. c.) Single Chest CT scan ~ 5.8 mSv (CXR ~ 0.02 mSv, so = 300 CXRs). Flexible bronchoscopy 1.) suspicion of airway abnormality. 2.) localized radiology changes. 3.) suspicion of inhaled foreign body. 4.) eval of aspiration lung disease. 5.) micro studies and lavage (BAL).

ETIOLOGY
In children with specific cough, further investigations may be warranted, except when asthma is the etiologic factor.

Cough is the most common presenting symptom in patients presenting to doctors in US and Australia. Viral URIs, which also cause cough, are said to account for 80 percent of childhood asthma exacerbations. 7yo female with known RAD presents with cough and wheezing.

ETIOLOGY
Upper Airway Disorders and Cough Upper airway cough syndrome (aka post-nasal drip) well documented in adults. In children, relationship between nasal secretions and cough is more likely linked by common etiology (infection or inflammation). Abnormal sinus radiographs found in 18-82% of asymptomatic children. No RCTs on therapies for upper airway disorders in kids with improvement of nonspecific cough as outcome measurement.

ETIOLOGY
GERD and Cough PROOF that GERD causes chronic cough in kids is rare. Infants often regurgitate, but few well infants cough with these episodes. Available prospective studies of chronic cough in kids suggest that GERD is infrequently the SOLE cause.

ETIOLOGY
Airway Lesions and Cough Prevalence of airway lesions found in asymptomatic children is unknown. Relationship of cough to airway lesion can only be postulated: Airway malacia impedes clearance of secretions; potential for pneumonic process distal to lesion

ETIOLOGY
Environmental Pulmonary Toxicants Increases susceptibility to respiratory infections Increases coughing illnesses Close association to tobacco smoke exposure, especially in association with asthma. 15yo female with cough for past month, noticed by parents that only occurs after home from school.
In all children with cough, exacerbating factors such as ETS exposure should be determined and interventional options for the cessation of exposure advised and initiated.

ETIOLOGY
Chronic Nocturnal Cough Unreliability and inconsistency of reporting. Often used as a direct indicator of asthma. Community based study revealed only a third of children with isolated nocturnal cough had asthma. No studies that objectively document that nocturnal cough is worse than daytime cough in uncontrolled asthmatics.

ETIOLOGY
Respiratory Infections and Postinfectious Cough Postviral cough refers to presence of cough after acute viral URI. Unstudied natural history beyond 25 days. Re-infection (when not completely recovered) may result in appearance of prolonged coughing. Total respiratory illnesses per person year ranges 5-8/yr (<4yrs) and 2.4-5/yr (10-14yrs). Classic infections (pertussis, Mycoplasma) typically cause cough with other symptoms, but consider antibiotics and vaccination as modifiers.

ETIOLOGY
Psychogenic Cough AKA habit cough, tic cough, psychogenic cough. Behaviorial association.

Inhalation of Foreign Body Presentations usually acute, but chronic cough may be presenting symptom of missed FB inhalation. Normal CXR does not exclude. Specific history should be sought.

ETIOLOGY
Parental Expectations Parental expectations as well as the doctors perceptions (of said expectations) influences consulting rates and prescription use. Use of OTC meds and frequency of doctors visits were less likely with more highly educated mothers. Parental concerns can be extreme and include fear of child choking and dying, SIDS, asthma attack, permanent chest damage.
In children with nonspecific cough, parental expectations should be determined, and the specific concerns of the parents should be sought and addressed.

Types of coughs
Dry or non productive cough Phlegmy or productive cough Croupy or barking cough Cough with wheezing Pertussis or cough with a whoop GERD or cough with choking

Dry or nonproductive cough


Short bursts of incessant cough Occurs daytime as well as nighttime Associated with hoarseness of voice, pain while swallowing and on external pressure Nocturnal dry cough is aggravated in supine position due to post nasal drip Acute dry cough is caused by upper respiratory infections due to virus including Flu virus, bacterial infections including Streptococcus, H Influenzae and Chlamydia Chronic dry cough could be due to enlarged tonsils, adenoids with post nasal drip or intraluminal or extraluminal obstruction in upper airway eg. Endobronchial/ paratracheal LNs
Pharyngeal irritation directly is unlikely to induce cough because the innervation is Glossophayngeal & not vagus.

Phlegmy or Productive cough


Productive cough is due to catarrh due excessive production or non clearance of mucus from upper/ lower airway It could be infective or noninfective Infective productive cough could be due to infection in upper airway as in paranasal sinusitis or lower airway as in pneumonia or bronchiectasis Non infective productive cough could be due to allergic catarrh or due to thick tenacious phlegm as in cystic fibrosis Cough is seen daytime as well as night time

Croup or barking cough


Sudden onset spasmodic non productive cough with a barking quality Mostly occurs in early half of night Mostly occurs in children below 3 years of age Generally preceded by mild corryza with/ without fever of short duration Although dramatic in onset & presentation, child doesnt appear toxic or in pain or distress. No dysphagia. Very few children have recurrences till age of 3 years. X-ray neck AP view shows subglottic narrowing of airway: Steeple sign Toxic child with dysphagia, dysphonia should have X-ray neck Lateral view to r/o epiglottitis which is a medical emergency.

Pertussis or cough with a whoop


Prolonged cough with short outbursts of cough ending with a sound of whoop Lasts from a few weeks to months even after specific treatment with appropriate antibiotics. Severity of cough esp in small infants can lead to conjunctival , oral mucosal bleed, intracranial bleed can lead to convulsions or loss of cosciousness. A bout of cough may lead to severe vomiting as well as poor intake of food, leading to malnutrition

GERD or cough with choking


Coughing associated with feeding events More common in supine feeding- more in bottle-fed than breast fed infants. Occurs in neonates and may continue till late infancy when child starts to feed in sitting position esp semisolid & solid feeds Typically starts within few minutes of feeding with mild clearing throat sounds leading to head bobbing followed by bout of vomiting or cough as mouth fills with milk rising from the esophagus. Head bobbing may even lead to retraction of neck . Severity of GERD is classified in terms of frequency as well as degree of reflux. It occurs due to physiological laxity of lower esophageal sphincter with acidic stomach contents coming into esophagus
The cough is due to stimulation of chemoreceptors in the distal airway & Vagal innervated receptors in the esophagus

Why should we treat cough?


It is obvious that the process of cough is beneficial and helps to clear mechanical or chemical irritants in the respiratory tract. However the large pressures & velocities generated in the airways are also responsible for many of the complications of cough, including hoarseness, excessive perspiration, urinary incontinence, rib fractures, musculoskeletal pain, exhaustion, headache, dizziness & self-consciousness. The nocturnal cough with/ without post nasal drip leaves the child insomnic with daytime somnolescence & hyperkinetic behavior.

Choice of cough medications


The purpose of cough medications is alleviation of symptoms. They are always add-ons to specific medications such as Antibiotics, Bronchodilators, antiallergics eg antihistaminic & interleukin receptors inhibitors eg Montleukast or anti-inflammatory eg steroids Cough medications are given as cough suppressants, decongestants, expectorants & mucolytics. They are available as tablets, syrups or lozenges

Cough suppressants
Cough suppressants prevent or stop coughing Cough suppressants cross the blood brain barrier & act on the center in the medulla that controls the cough reflex i.e. they act centrally They are narcotic derived e.g. Codein, pholcodein, Noscapine and non addictive narcotic like Dextromethorphan or non narcotic like Benzonatate They are useful to suppress dry cough, nocturnal cough and pertussis. They are prone to be abused They are not safe below 6 years of age.

Cough suppressants
Dextromethorphan is the commonest cough suppressant available either alone or in combination with antihistamines or decongestants Derived from morphine, it is a narcotic antitussive but has no analgesic or addictive property Although it is as effective as Codein as an antitussive in adults, its efficacy is no better than placebo Although it is non addictive in therapeutic dose , in very high dose it is used for recreation and is prone to be abused. Dosage: 0.5 mg/kg/dose 3-4 times a day Codein: Centrally acting narcotic antitussive available either alone or in combination with antihistmines. Dosage: 0.3mg/kg/dose 2-3 times/day Noscapine: Non addictive narcotic antitussive.

Mucokinetic agents
These are various agents which help to keep the mucus thin and helps the mucociliary mechanism to expel the thick mucus. Act on the afferent wing of cough reflex, either as: Expectorants : stimulate body to hydrate & thin the mucus eg. Guiphenesine Mucolytic agent: Helps to make mucus thin e.g. oral Carbocystein, Ambroxol, Bromhexine or inhaled acetylcysteine. Adhesives / surfactants: Reduces affinity between secretions & biological surfaces eg. Ammonium chloride, potassium iodide

Combination cough medications


Common available combinations: Antitussive + Antihistamine Decongestant + Antihistamine Decongestant + Mucolytic Expectorant + Mucolytic Expectorant + Antiadhesive Expectorants + Brochodilator Combinations that should be banned Montlukast + Expectorants Expectorants + Zinc / Calcium Mucolytic + Amoxycillin

Herbal medicines & Home remedies


Mostly cough suppressants act as demulsifying agents soothing for throat Contain various combinations of honey, tulsi, ginger, methi. Recent preparations with dry ivy leaf extract Give temporary relief Do not treat underlying cause Generally safe & non addictive

Fever
Elevation of body temperature above normal range of 36.5 37.5 C (98100 F) due to elevated temperature regulatory set point is fever. Elevation of body temperature greater than or equal to 41.5 C (106.7 F) due to elevated temperature regulatory centre is hyperpyrexia which is fever. Elevation of body temperature without elevated temperature regulatory set point as in elevated environmental temperature or heat stroke is hyperthermia
In hyperthermia the body temperature rises above its set point & hence is not fever!

Thermoregulatory mechanism
The brain orchestrates heat effector mechanisms via the Autonomous Nervous system: Increased heat production: by increased muscle tone, shivering hormones like epinephrine Prevention of heat loss vasoconstriction.
This temperature regulation is controlled in the hypothalamus

Thermoregulatory centre & afferent & efferent arms


The preoptic region, in & near the rostral hypothalamus, acts as a coordinating center. The preoptic area contains neurons that are sensitive to subtle changes in hypothalamic or core temperature & also receive somatosensory input from spinal & skin thermoreceptors & integrate central and peripheral thermal information

Mechanism of fever
Fever & Hyperpyrexia result from elevation of thermoregulatory set point in response to chemical mediators called pyrogens. Pyrogens are generally immune mediated cytokines eg. IL 1, IL 6, TNF generally released from macrophages engulfing various pathogens. These cytokines then bind with endothelial receptors on vessel walls activating the arachidonic acid pathwayformation of PGE2 mediator of fever
(COX2)

by acting on the preoptic area of hypothalamus fever response

Body responses to temperature variations


Effector
Smooth muscles in arterioles in the skin. Sweat glands

Response to low temperature


Muscles contract Vasoconstriction. Extremities can turn blue and feel cold and can even be damaged (frostbite). No sweat produced.

Response to high temperature


Muscles relax vasodilation. More heat is carried from the core to the surface lost by convection & Skin turns red.

Glands secrete sweat onto surface of skin evaporates, it takes heat from the body
Muscles relax, lowering the skin hairs and allowing air to circulate over the skin convection and evaporation.

Erector pili muscles in skin Skeletal muscles

Muscles contract, raising skin hairs and trapping an insulating layer of still, warm air next to the skin. Shivering: Muscles contract & relax repeatedly, generating heat by friction & metabolic reactions

No shivering.

Adrenal & Glands secrete adrenaline and thyroxine thyroid glands respectively increases the metabolic rate in different tissues generating heat. Behavior Curling up, huddling, finding shelter, putting on more clothes.

Glands stop secreting adrenaline & thyroxine. Stretching out, finding shade, removing clothes

Why fever?
Fever is a very energy consuming process that evolution has preferred to persist why? It is presumed that fever improves host immune response: Increased mobility of leukocytes Enhanced leukocytes phagocytosis Endotoxin effects decreased Increased proliferation of T cells
Those with bacterial infection are seen to have lower mortality when associated with fever.

Why treat fever?


Although fever seems to be beneficial to the host, the discomfort associated with fever eg. Malaise, headache, tachycardia, hypertension necessitates treating the fever. Certain high risk patients eg. Congenital heart diseases esp with LR shunt, certain metabolic disorders & those with H/O febrile convulsions as well as epilepsy benefit from controlling fevers.
Fever controlling medications do not alter the course of the disease causing the fever

Treatment of fever
Physical methods:
Sponging natural sweating areas of the body i.e. head, arms, legs, axilla & scrotum. Sponge with plain water or with salt or cologne added. Preferable to use warm water. temp body-water = 2OF Avoid blocking sweat pores with oil, woolen clothes. Keep the surroundings cool Keep well hydrated

Treatment of fever
Medications: Paracetamol: aniline analgesic which is not an NSAID. Weak inhibitor of
COX.

Rapidly absorbed with/ without food Onset of action 11minutes Duration of action 4 hours. Dose related liver toxicity.
Paracetamol in regular dosage safe in G6PD deficiency

Ibuprofen: Nonselective COX inhibitor NSAID .Rapidly absorbed with/ without food . Rapid onset of action . Duration of action 8 hours . Because of nonselective COX inhibition G I disturbance is common.
Ibuprofen not safe in G6PD deficiency

Other NSAIDs
1) NONSELECTIVE COX INHIBITORS

- acetylsalicylic acid at high dosage - diclofenac - ibuprofen - ketoprofen - flurbiprofen - indomethacin - piroxicam - naproxen 2) COX-1 SELECTIVE INHIBITORS - acetylsalicylic acid at low dosage 3) MORE COX-2 SELECTIVE INHIBITORS - nimesulid - nabumeton 4) COX-2 SELECTIVE INHIBITORS - celecoxib - etorcoxib

Commonly used drugs in cough and cold preparations

Chlorpheniramine maleate
Class - Antihistamines

Antihistaminic action :
Blocks the action of histamine (a substance causes allergic symptoms) Promptly relieves symptoms in Rhinitis (sneezing, itching of eyes, nose & throat)

Anticholinergic action:
reduce secretion - Rhinorrhoea

Chlorpheniramine maleate
Chlorpheniramine relieves
Red, itchy, watery eyes Sneezing Itchy nose or throat Runny nose (Rhinorrhoea)

Chlorpheniramine helps control the symptoms of Common Cold

Phenylephrine Hydrochloride
Nasal Decongestant
Decongestants are the drugs of choice for a stuffy, congested nose Decongestants act by narrowing the blood vessels in the nose, leading to decreased

blood flow in the nasal tissues and reduced


leakage of fluid from the nose

Phenylephrine Hydrochloride
Nasal Decongestant
Direct Sympathomimetic

Selective alpha1 agonist action


Act on alpha adrenergic receptors in the mucosa of the respiratory tract producing vasoconstriction which results in shrinkage of swollen mucus Relieves Stuffy Congested Nose

Paracetamol
Paracetamol is one of the most popular and widely used drugs for the treatment of pain and fever Central Analgesic Action raises pain threshold Anti-pyretic action Good safety profile

Relieves fever, sore throat and body ache

Newer mechanism of Action for Paracetamol


Cananbinoids have a role in modulation of pain (decrease the pain) Active metabolite of PCM goes and bind to cannabinoid receptor

Analgesic effect of paracetamol is due to the indirect activation of cannabinoid CB(1) receptors

CNS Drug Rev. 2006 Fall-Winter;12(3-4):250-75.

Caffeine
Methyl xanthine alkaloid

Consumed as beverages
CNS Stimulant primarily affect the higher centers Produces
Sense of well being, Alertness,

Beats bordem,
Allays fatigue, Improve performance

Dextromethorphan Hydrobromide (DMR)


Non - narcotic cough suppressant (anti tussive).

Acts centrally on cough centre, (Medulla) and elevates the threshold for coughing.
Equipotent to codeine in depressing cough reflex.

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Dextromethorphan Hydrobromide (DMR)


Average dose is 10 to 30 mg 3 to 6 times daily. Has no expectoration action and does not inhibit ciliary action. Rapidly absorbed from G.I. Tract. Exerts effect within 15-30 minutes after oral administration. Duration of action is 5-6 hours. Metabolized in the liver. Sales Training

Cough suppressants with equipotent doses


Dextromethorphan Codeine 10 mg 15 mg

Noscapine
Pholcodeine

15 mg
10 mg

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Favorable Features of Dextromethorphan Hydrobromide


Equipotent antitussive to Codeine, Pholcodiene which are narcotic. No addictive properties.

Does not cause CNS depression nor it affects respiratory rate.

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Favorable Features of Dextromethorphan Hydrobromide

Does not cause drowsiness, constipation unlike codeine.

Is safe & effective.

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Guaiphenesin
Most commonly used expectorant. Often used singly or in combination. Readily absorbed from GI tract

Increases the output of respiratory tract fluids, this helps to liquefy the thick mucus.
Though not a cough suppressant reduces the intensity and frequency of dry or productive cough.

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Guaiphenesin
Reference From a study in 239 patients it was reported that Guaiphenesin reduced cough intensity and frequency in patient with dry or productive cough and helped to thin sputum.
RE Robinson et al, Robins, Curr ther Research, 1977 : 22 ; 284
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