Nausea and vomiting

This chapter is only vaguely relevant to Section O2(iii) from the 2017 CICM Primary Syllabus, which expects the exam candidate to "Describe the pharmacology of drugs with anti-emetic activity". The tenuous thread connecting this page to reality are Question 3 from the first paper of 2013 and Question 10(p.2) from the first paper of 2010,  which asked the candidates to describe the physiology and neural integration of nausea and vomiting.  This probably belongs in the same section as a discussion of antiemetics, as it would occupy the same cognitive shelf for the casual reader. 

In summary:

Neurology of nausea and vomiting:

  • Stimuli: toxinaemia, sensory stimuli, visceral afferents, psychological
  • Sensors: Chemoreceptor trigger zone, sense organs (eg. visual, olfactory and gustatory), vestibular labyrinth, mechanoreceptors in the GIT.
  • Afferents: vagus, sensory tracts, vestibulocochlear nerve, central descending
  • Central processors: Nucleus of the solitary tract and chemoreceptor trigger zone both feed into the "central pattern generator" which coordinates the mechanical act of vomiting
  • Efferents: Vagus (to stomach and small intestine), lower cranial nerves (to face and oropharynx), somatic motor fibres (to chest/abdominal muscles), sympathetic nervous system (tachycardia, vasoconstriction, sweating)

Mechanics of vomiting:

  • Phase 1: giant retrograde peristaltic contraction,  
    with closed lower oesophageal sphincter
  • Phase 2: increased intraabdominal pressure due to muscle contraction,  
    with closed lower oesophageal sphincter
  • Phase 3: abdominal wall contraction, pyloric contraction, 
    with open lower oesophageal sphincter

The best recent reference for the neurology would have to be the chapter by Horn for Nausea and Vomiting (2017, p.15-25)

The neurology of nausea

Like many things in physiology (hello, afterload), there's no agreed-upon definition for what "nausea" is, other than the "unpleasant painless subjective feeling that one will imminently vomit" (Singh et al, 2015). Vomiting is not essential in nausea, and nausea is not a necessary precondition for vomiting. Most authorities on the subject, when asked to explain the neurological basis of nausea, will wave their hands descriptively and talk about complex mechanisms integrating psychological states with the autonomic nervous system, endocrinology, intestinal motility, etc etc.

 There appears to be a dynamic nausea threshold. Stern (2002) describes it as a constantly shifting parameter, which can increase or decrease the nauseogenicity of any given stimulus. Under the right conditions, things that were not previously nauseating might suddenly cause vomiting. You might not normally get carsick, until you take a trip with just the right person.

Not a lot is known about where this sensation originates from. It appears as if many of the nauseating stimuli need to pass through the nucleus of the solitary tract, and it integrates all the inputs to coordinate vomiting. It also seems to project to the upper CNS, which makes it an attractive candidate for the Master of Nausea. Or at least the NTS seems important because antinausea drugs all seem target its monoaminergic neurotransmitter connections to the higher brain areas. However, the neurology of this process is far from settled. We are in that shadowy territory of neuroscience where people can successfully publish their interpretations of foggy low-resolution FMRI data. As the result, on the neural map of nausea and vomiting there is a lot of terra incognita, unfinished PhDs lurking in its briny depth.

Physiology of vomiting

In Question 3 from the first paper of 2013 the examiners expected candidates to "detail the pathways involved (afferent and efferent limbs) and describe the relationship with the coordinating centres" involved in vomiting. The stem described this as the "neural integration" of vomiting. In the same sense, the baroreceptor reflex is the neural integration of hypotension. In short, the college were looking for a stereotypical answer to the question, "how does the vomiting reflex work". The best reference to answer this is actually a 1986 book chapter by Willems & Lefebvre, but it would be rather difficult to get a hold of this ancient out-of-print textbook. Fortunately, Josef Donnerer's chapter "The emetic reflex arc" from Antiemetic therapy (2003) is somehow available for free online. 

There's a couple of different ways to represent this system, one of which is to use the classical pattern applicable to all reflex arcs:

  • Stimuli
    • Bloodstream toxins
    • Sensory stimuli (any of the senses!)
    • Gut distension or noxious chemical content
    • Psychological stimuli
  • Sensors:
    • Chemoreceptor trigger zone (part of the area postrema, one of the circumventricular organs which lay outside the blood-brain barrier) 
    • Sensory inputs
      • Visual, olfactory and gustatory stimuli
      • Vestibular labyrinth
    • Gastrointestinal tract:
      • Mechanoreceptive neurons in the submucous plexus
      • Chemoreceptors in the vagal sensory ganglia
    • Descending systems (pain, anxiety, fear)
  • Afferent pathways:
    • Vagus nerve (to the NTS): main receptors involved are 5-HT3, D2, H1 and muscarinic.
    • Vestibular apparatus: main receptors involved are H1 and muscarinic.
    • Ill-defined central pathways (to the CTZ): main receptors involved are 5-HT3, D2, H1 and muscarinic.
  • Central processor:
    • Nucleus of the solitary tract (NTS) integrates inputs from:
      • vagus nerve
      • the vestibular apparatus
    • Chemoreceptor trigger zone (CTZ) integrates inputs from:
      • the higher CNS
      • vestibular apparatus
      • direct action of blood-borne toxins
    • "Central pattern generator", the exact position of which is unknown, but thought to be in the reticular area dorsomedial to the retrofacial nucleus, integrates the inputs from
      • Nucleus of the solitary tract
      • Chemoreceptor trigger zone
      • Higher cortical areas
    • Neurotransmission in these centres is mediated by:
      • Muscarinic acetylcholine receptors
      • Dopamine receptors
      • 5-HT3 serotonin receptors
  • Efferent pathways:
    • Descend from the central pattern generator to:
      • Vagus nerve
      • Hypoglossal nerve
      • Glossopharyngeal nerve
    • Ascend from the central pattern generator to:
      • hypothalamus and insula, which coordinate the sympathetic responses
      • Motor cortex, which coordinates the somatic motor response
  • Effectors:
    • Somatic (long tracts and cranial nerves):
      • Motor nerves to the respiratory muscles, abdominal muscles, oropharynx and tongue
    • Vagal:
      • Motor control of retrograde peristalsis
      • Relaxation of the lower oesophageal sphincter
      • Gastric and oesophageal contraction
    • Sympathetic nervous system, via the CNS:
      • Sweating
      • Salivation
      • Peripheral (cutaneous) vasoconstriction
      • Tachycardia

Unfortunately, this unordered point-form list is too long to present in a quick CICM exam answer. A diagram is probably better, as it would reduce the total number of words a person needs to write, and cut precious minutes. A whole range of similar-looking oversimplifications are available from a basic Google image search, and as always Deranged Physiology never shies from adding to a needlessly inefficient abundance:

Neural integration of vomiting

Of course one could never hope to include every possible connection and pathway in something like this, which makes any attempt to graphically represent this subject into a compromise between readability and accuracy. Fortunately, it does not seem as if the CICM examiners expect very much from the candidates when it comes to the neural integration of this process. Their comments for Question 3 were "afferent pathways to the vomiting centre include stretch and chemoreceptors located throughout the GIT via vagal and sympathetic nerves, pharyngeal touch receptors via glossopharyngeal nerves etc".

Mechanics of vomiting

At least the engineering aspects of vomiting are a lot easier to study, as they are much more straightforward, being the interaction of pressures in an arrangement of tubes. 

  • Phase 1 (the prodrome): This is the beginning of the end for your last meal; a process where, under the influence of vagal efferents, the enteric nervous system coordinates a "giant retrograde contraction" which propels intestinal contents into the stomach, which relaxes to accommodate it as a part of the same reflex. From how far down in the gastrointestinal tract does this contraction begin? Reader, you would be surprised. According to Lang (1990), half of the small intestine length may be involved, meaning you will become reacquainted with the contents of the uppermost 2-3 metres of your duodenum and jejunum. 
  • Phase 2 (retching): With the stomach now full of intestinal contents, the next part of the process requires it to be positioned near the lower oesophageal sphincter. Spinal motor efferents to the crural diaphragm and the abdominal muscles contract to increase the pressure in the abdominal cavity, concentrating the stomach contents under the diaphragm. Because the crural diaphragm also contracts and the lower oesophageal sphincter remains closed, abdominal contents does not escape.
  • Phase 3 (expulsion) is the final phase, characterised by the relaxation of the lower oesophageal sphincter and the contraction of the muscular pylorus and abdominal wall. The crural diaphragm remains relaxed, and gastric content can be expelled freely up the oesophagus. Because the pylorus contracts and the abdominal pressure is raised, there is nowhere else for it to go.

References

Horn, Charles C. "The physiology of vomiting." Nausea and Vomiting. Springer, Cham, 2017. 15-25.

Parkes J.D. (1986) A Neurologist’s View of Nausea and Vomiting. In: Davis C.J., Lake-Bakaar G.V., Grahame-Smith D.G. (eds) Nausea and Vomiting: Mechanisms and Treatment. Advances in Applied Neurological Sciences, vol 3. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-70479-6_12

Singh, Prashant, Sonia S. Yoon, and Braden Kuo. "Nausea: a review of pathophysiology and therapeutics." Therapeutic advances in gastroenterology 9.1 (2016): 98-112.

Stern, R. M. "The psychophysiology of nausea." Acta Biologica Hungarica 53.4 (2002): 589-599.

Horn, Charles C. "Why is the neurobiology of nausea and vomiting so important?." Appetite 50.2-3 (2008): 430-434.

Napadow, Vitaly, et al. "The brain circuitry underlying the temporal evolution of nausea in humans." Cerebral cortex 23.4 (2013): 806-813.

Donnerer, Josef. "The emetic reflex arc." Antiemetic therapy (2003): 1.

Willems, J. L., and R. A. Lefebvre. "Peripheral nervous pathways involved in nausea and vomiting." Nausea and vomiting: Mechanisms and treatment. Springer, Berlin, Heidelberg, 1986. 56-64.

Koga, Tomoshige, and Hiroyuki Fukuda. "Descending pathway from the central pattern generator of vomiting." Neuroreport 8.11 (1997): 2587-2590.

Lang, Ivan M. "Digestive tract motor correlates of vomiting and nausea." Canadian journal of physiology and pharmacology 68.2 (1990): 242-253.