Dr.Panchadcharam Harinath MD,
Academia Grandiosa Medicinae,
Gautam Nagar, South Delhi.
Dr.Karishma Harbada MD,
J J Hospital, Mumbai.
Abstract
Emesis is a well coordinated reflex closely controlled centrally & peripherally. The anatomic functional components are located in Rhomboencephalon, formatio reticularis spinalis & limbic brain. Dopamine, Serotonin, Acetylcholine, Histamine, endogenous opioids & substance-P are the main neurotransmitters involved in the neurons of emetic reflex. There are hundred of Aetiologies to cause nausea & vomiting. Diseases & past history of patients are of utmost importance to reveal the aetiology. Evaluation of emesis includes other diagnostic modalities when the aetiology can not be diagnosed at primary assessment of patient. Elimination of causative agent is the first step of management & other therapeutic modalities can be used when the first step of management is unsatisfactory.
Key words
Emesis, Nausea, reflex, Rhomboencephalon, formatio reticularis spinalis, limbic brain, Dopamine, Serotonin, Acetylcholine, Histamine, endogenous opioids, substance-P, aetiology, dehydration, electrolytes, Chemoreceptor trigger zone, Nucleus tractus solitarius, Nucleus vestibularis, Spinoreticular fibres, Vomiting centre, Circumventricular organs, blood brain barrier, Enkephalins, Meniere’s disease, Labyrinthitis, pyelonephritis, urolithiasis, dysmenorrheal, , hyperemesis gravidarum, Melena , haematemesis, pararexia, Vertigo, nystagmus, Metabolic alkalosis, Hypokalemia, Oesophagitis, bulimics, Boerhaave's syndrome, Mallory-Weiss syndrome, Aspiration pneumonitis, atelectasis, abscesses, anamnesis morbid, vitae
Introduction
Vomiting or Emesis in physiological aspects is not a motility disorder of Gaterointestinal tract but an adaptive reflex to evacuate gastric contents; however Emetic reflex plays a pivotal role in pathologic conditions Eg- in food poisoning vomiting will evacuate GIT contents to prevent absorption of toxins but such adaptive process leads to dehydration & electrolytes disturbances. Vomiting acts as a protective reflex even though Nausea & vomiting that is chronic in nature reminds an underlying pathologic process & affects patient’s quality of life. A complete explanation to Physiologic & pharmacologic implications of emetic reflex is not detailed in any text book. This article deals more or less completely with the Physiologic & pharmacologic aspects of the emetic reflex & also emphasizes on physiologic as well as clinical aspects of vomiting such as Aetiology, Differential diagnosis, Evaluation & management.
Physiological aspects of emetic reflex
Emetic reflex is closely monitored by neural & humoral factors. Vomiting can be triggered either centrally or peripherally however essential centre to coordinate the reflex is located in brain stem.
There are 6 anatomic functional components to operate emetic reflex as given below1,
1-Vomiting centre (VC)
Vomiting centre (VC) which is a part of lateral reticular formation of medulla oblongata contains M1 cholinergic receptor, Miu opioid receptor & nk-1 substance-P receptor.
It receives inputs from the following components given below.
2-Chemoreceptor trigger zone (CTZ)
Chemoreceptor trigger zone (CTZ) is situated in area postrema which is also a component of Circumventricular organs2. The relative permeable regions of blood brain barrier are collectively called Circumventricular organs. CTZ is very rich in receptors such as dopaminergic receptors (D2), serotoninergic receptor (5HT3), opioid receptor (delta), substance-P receptor (nk-1), and angiotensin receptor (AT-II). Functional significance of all the receptors in CTZ is not fully understood.
3-Nucleus tractus solitarius (NTS)
Nucleus tractus solitarius (NTS) is the visceral sensory nucleus receives afferents from Cranial nerves VII, IX & X. It’s the relay station of Gag reflex (IX). It contains histaminergic receptors (H1) & M1 cholinergic receptor. Nervus Vagus is the main visceral efferent posses serotoninergic receptor (5HT3) that is responsible for peripheral stimulation of emtic reflex.
4-Nucleus vestibularis
Nucleus vestibularis(VN) receives afferents from Labyrinthus vestibularis & sends afferents to cerebellum. It contains histaminergic receptors (H1) & M1 cholinergic receptor too.
5-Spinoreticular fibres
Spinoreticular fibres are one of factors leads to emesis associated with Pain or physical injury. Reticular formation at spinal cord level receives short afferents from tractus spinothalamicus that carries pain stimulus to barin. Other mechanisms probably operates pain associated emesis are action of anti-nociceptive agents as Enkephalins on opioid receptors on CTZ or VC & activation of limbic brain by alteration in psychological state.
6-Limbic cortex
Limbic cortex is responsible for emesis associated with olfaction. Cortical afferents connect Lymbic system presumably accounts for emesis associated with unpleasant sight or emotional disturbances & also involved in the conditioned emetic reflex.
The reason why cannabinoids suppress vomiting is Probably CB1-tetra-hydro cannabinol receptors are located either in VC or CTZ; which still awaits proof3,4,5. But presence of these receptors in vagal afferents & their function in hunger & satiety is in experimental level, even though connection to emetic reflex is not still documented.
In pregnancy plasma concentration of catecholamines increase which can stimulate D2 receptors in addition emerging levels of hCG & sex steroids may sensitize these receptors in CTZ to multiply the effects of catecholamines. Altered psyche may play a role through limbic brain in pregnancy induced vomiting. In the case of Hyperemesis Gravidarum the above mentioned mechanisms run in hand to hand with ketonemia.
In dysmenorrhea increased levels of prostaglandins act on thrombocytes to increase serotonin which acts on CTZ to cause vomiting. The very same prostaglandins are the culprits to induce cramps & diarrhea in dysmenorrhea that’s why symptoms of dysmenorrhea can be controlled by NSAIDs.
Fig-1.The main neurotransmitters & the proposed inter connections between the emetic reflex components. (Designed by Dr.P.Harinath MD & Dr.Karishma Harbada MD)
VC-Vomiting centre, CTZ-chemo-trigger receptor zone, NTS-Nucleus tractus solitaries, VN-Nucleus vestibularis, 5HT-5 hydroxy tryptamine, PGs-Prostoglandins, hCG-Human chorionic gonadotrophin, ECLC-Entero-chromophin like cells, I-olfactory nerve, IX-Glossopharyngeal nerve, X-Vagus nerve, N.PLV- Nucleus posterior ventralis posterolateralis thalami.
Act of emesis
Emesis a well coordinated Visceral & somatic muscular phenomena characterized by reverse peristalsis of intestine to evacuate materials into gaster, then thoracic, abdominal & diaphragmatic muscles contract to raise the intra-abdominal pressure against closed glottis which prevents aspiration. Reversal of the thoracic pressure gradient by the synchronous contraction of inspiratory and expiratory muscles along with raised intra-abdominal pressure expulse the gastric contents out6,7.
Vomiting usually is preceded by nausea a feeling of imminent emesis increases the salivary secretion probably has a biological significance by counteracting the effects of gastric acid to the oesophagus by salivary bicarbonates which may lead to hypertrophy of salivary glands in patients with chronic recurrent vomiting eg-bulimia
Aetiology of emesis8
A-Intra carnial, ear & psychiatric causes
Increased intracranial pressure (Neoplasm, encephalitis, hydrocephalus), closed trauma, cerebrovascular insults, Migraine, Meningitis
Meniere’s disease, Labyrinthitis, otitis media, Motion sickness
Bulimia & other Psychogenic vomiting
B-GIT & Hepatobilio-pancreatic causes
Organic disorders-Peptic ulcer, Gasteroenteritis, GERD, Appendicitis, Cholecystitis/cholangitis, Hepatitis, Inflammatory bowel disease, Pancreatitis, Peritonitis.
Functional disorders- Intestinal pseudo-obstruction, Gastroparesis, Irritable bowel syndrome & functional dyspepsia.
Obstruction-Adhesions, achalasia, intussusception, Malignancy & Pyloric stenosis
C-Cardio-pulmonary & URT causes
Pharyngitis, tonsillitis, Pneumonia, pulmonary abscess, pleurisies, inferior wall MI & severe heart failure with hepatic congestion.
D-Genitourinary causes
UTI/pyelonephritis, urolithiasis, dysmenorrhea, premenstrual syndrome, pelvic inflammatory disease & ovarian tumors.
E-Infectious, inflammatory & toxic causes
Bacterial & viral infections, food born toxins, heavy metal poisoning, pesticides poisoning & other chemicals poisoning.
F-Metabolic & endocrine causes Adrenal disorders, Diabetic ketoacidosis, Parathyroid disorders, Pregnancy, hyperemesis gravidarum, Thyroid disorders, Uremia
G-Iatrogenic & pharmacologic causes
Antiarrhythmics, Antibiotics, Chemotherapeutics, Digoxin, Ethanol overdose, Nonsteroidal anti-inflammatory drugs, Opiates, Radiation therapy, anesthesia, invasive procedures, post operative.
Anamnestic & physical clues for Differential diagnosis9,10
Instrumental & laboratory investigations for differential diagnosis9,10
1-GIT conditions-
Abdominal Röntgenography- PUD, Ileus or urolithiasis
Abdominal sonography & CT- malignancy, other obstructions & appendicitis
Endoscopy- PUD & GERD
Fecal occult blood test- PUD & malignancy (melena)
2-Hepatobiliopancreatic conditions-
Liver function test-AST, ALT, Phosphatase, Clotting profile & serum albumin, bilirubin or urea-hepatitis
Serum lipase-pancreatitis
Abdominal sonography & CT- pancreatitis & complications, liver abscess, cyst or malignancy & cholecystitis
CBC/CRP-inflammatory conditions eg- cholecystitis
3-Endocrine & metabolic conditions-
Hormone assays-T3, T4, TSH-thyroid disorders
Corticoids & metabolites-adrenal disorders
Testosterone, oestrogens & prolactin- Gyneco-endocrine conditions eg-PCOD or Hormone secreting tumors
PTH-parathyroid disorders
Electrolytes & others- Ca2+, K+, Na+, acid-base status, ketones- DM ketosis or hyperemesis gravidarum
Pregnancy test-hChNH
4-CNS disorders-
CT & MRI of head- Brain tumor or abscess.
5-miscellaneous-
Renal function test-RF
ECG-Inferior MI
Management of Vomiting1,3,4,11
Algorithm of vomiting management is shown in the diagram below.
1-When diagnosis is made the primary & effective management is elimination of causative factor if possible Eg-drugs & toxins
2-Decompression technique can be used in surgical conditions eg-ileus
3-Anti-emetics can be used when the steps above are not satisfactory or temporarily
Classes of antiemetics
a- Histamine (H1) antagonists
DOC for prevention of motion sickness contraindicated in night workers or drivers because of their sedatory side effect
b- Antimuscuranic drugs
DOC for prevention of motion sickness side effects include dry mouth, dry eyes, urinary retention & constipation
c- Dopamine antagonists
DOC for pregnancy induced emesi(metachlorpromide) & anti-Parkinson therapy induced emesis(Domperidone). These drugs are prokinetics that are used in GERD, diabetic gastro-paresis, hypokinetic dyskinesia of bowel
d- Serotonin antagonists DOC for cancer chemotherapy induced emesis, also used to control few symptoms of carcinoid syndrome
e- neurokinin-1 antagonist (Sub-P) - vofopitant
New drug successfully used in chemotherapy induced as well as post operative emesis
f- Cannabinoids –nabilone & dronabinol
g- Corticosteroids
Drugs which can be used in cases where emesis is resistant to other drugs, especially chemotherapy induced ones. These two drugs are also used as non specific appetite stimulants in patients with cachexia
Complications of vomiting
Complications due to loss of secretions
1-Dehydration
2- Metabolic alkalosis
3-Hypokalemia
Complications due to loss nutrients & loss of appetite
1-vitamin deficiencies
2-mlnutrition
Complications due to gastric acid
1-Dental caries & erosions
2-Corrosive Oesophagitis
3-corrosive strictures
4-acid burns of hands in bulimics
5-sialadenohypertrophy
Complications due to acid + pressure
1- Boerhaave's syndrome
2-Mallory-Weiss syndrome
Complications due to aspiration
1- Aspiration pneumonitis
2-atelectasis
3-abcsesses
Conclusion
Neurophysiology of emetic reflex is the basis for the initial differential diagnosis & management of nausea & vomiting. Chronic nausea & vomiting are alarming signals to underlying pathologic process. Evaluation of nausea & vomiting starts with the anamnesis morbi & vitae of patients to diagnose the etiology, further evaluation is needed when diagnosis is not possible with the first assessment. When vomiting is managed its dangerous complications such as dehydration, electrolytes –acid-base dysbalances, Boerhaave's syndrome, Aspiration pneumonitis should be born in mind to prevent the morbidity & mortality of patients.
References
1- Michael Neal, J; Medical Pharmacology at a glance, Blackwell Science, 4th edition. 2003. 67-67.
2- Werner Kahle; Nervous system & sensory organs, Thieme, 2003. 286-287.
3- Rang, H. P; Pharmacology, Churchill Livingston, 3rd edition, 1995.393-396.
4- Heinz Lullmann, Klaus Mohr; Color atlas of Pharmacology, Thieme, 2nd editon, 2000. 330-331.
5- James Kalat, W; Biological Psychology, Brooks/Cole, 5th edition. 1995, 352-357.
6- William Ganong, F; Review of medical physiology, Mc Graw Hill, 20th edition, 1999. 224-225.
7- Stefan Silbernagel, Florian Lang, Color atlas of Pathophysiology, Thieme,2nd edition, 2000. 140-141.
8- Walter Siegenthaler; Differential Diagnosis in Internal Medicine, Thieme, 1st edition, 2007. 42-42.
9- Douglas Collins, R; Differential Diagnosis in Primary Care, Lippincott Williams & Wilkins, 4th Edition. 2008. 322-325,450.
10- Adler Stephen, N; A POCKET MANUAL OF DIFFERENTIAL DIAGNOSIS, Lippincott Williams & Wilkins, 5th Edition. 2008. 116-119.
11- KEITH SCORZA, AARON WILLIAMS,DANIEL PHILLIPS,JOEL SHAW; Evaluation of Nausea and Vomiting. American Family Physician, 2007; 76:76-84.
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