Posts Tagged ‘ bradycardia ’

Strategies of Diving Mammals

Introduction

Diving to depth is a typical behaviour observed in many aquatic mammals such as; whales, otters, seals, walrus and many others. Such mammals are well adapted at diving. The Weddell seal for example, is able to dive for periods of 80 minutes and more. Compare this to the average 1-3 minutes in untrained humans and you can see that diving mammals have developed great abilities for diving to depths.

The two major problems associated with diving are; limited oxygen stores (limiting the length of the dive) and hydrostatic pressure (limiting the depth of the dive). Oxygen is an important factor during diving, an absence of oxygen (anoxia) means anaerobic respiration becomes the only source of energy. Anaerobic respiration consists only of glycolysis, which produces around 5% of the energy (ATP) produced during aerobic respiration. Such a great deficit in ATP production can damage brain cells and have fatal consequences. In anaerobic respiration, lactate is produced as a waste product. Normally (in aerobic conditions) the lactate is metabolised by the presence of oxygen, in its absence however, the lactate builds up and dissociates into lactic acid. This causes fatigue, which decreases swimming ability.

The dangers of hydrostatic pressure come include; physical damage as a result of the pressure (barotrauma). Especially gas filled spaces of the body such as the lungs and ears. As well as decompression sickness (referred to as ‘the bends’ in humans), caused by rapid changes in pressure.

Oxygen Stores

The main stores or oxygen in mammals are; the lungs, blood and muscle. Oxygen is also present dissolved in body tissue. In adept diving mammals such as the Weddell seal the primary store of oxygen is the blood (in haemoglobin), followed by the muscle (in myoglobin) and then the lungs. The Weddell seal actually exhales before performing a dive.

Having a large store of oxygen in the lungs causes some problems. A large lung volume can make the dive more energetically costly due to the extra energy spent negating the effect of increased buoyancy. Exhaling pre-dive decreases energy required to dive. Another factor to consider is that, being a gas filled space, the lungs are susceptible to hydrostatic pressure. At large enough depths, the pressure can cause the lungs to collapse. So, a large lung volume is not necessary for accomplished diving mammals and some will exhale before diving to reduce the lung volume further.

The blood has an excellent oxygen carrying capacity, oxygen binds with haemoglobin in the blood and this essentially dissolves the gas, thus reducing the volume and associated problems. Adept divers will have a greater volume of blood (and haemoglobin) and therefore are able to store more oxygen. Humans are typically able to store 15ml of oxygen per Kg of body weight, whereas accomplished divers can store anything between 40-70+ ml Kg-1.

Myoglobin is similar to haemoglobin, it is found in the muscles and transports oxygen, but it has a much higher affinity for oxygen. Large concentrations of myoglobin mean diving mammals are able to dive for much longer, therefore high levels of myoglobin are associated with accomplished divers.

No matter how great the ability to store oxygen, there will always be a time when oxygen stores are exhausted. This is known as the aerobic diving limit. It is the length of time an organism is able to dive and respire aerobically from stored oxygen. Dives longer than the aerobic diving limit are possible, but are often rare even in capable diving mammals. Taking the Weddell seal as an example, 80% of dives occur within the aerobic diving limit (about 18-20 minutes) but some still dive for periods of 80 minutes or more. This shows they have developed systems to help combat the buildup of lactate and the lack of oxygen which occurs during anaerobic dives of 20 minutes or more.

Extending Dives beyond the Aerobic Diving Limit

The body is still able to produce energy (ATP) without oxygen via glycolysis during anaerobic respiration but this is at an effective efficiency of 5%. Therefore glucose and glycogen stores (the body’s fuel) would be depleted at 20x the normal rate if glycolysis increased to match aerobic ATP production. Such an increase is known as the ‘Pasteur Effect’, but if the diving mammal is able to decrease metabolism, this might not be necessary.

Diving mammals are able to undergo metabolic depression, which reduces the energy demand of certain body systems by reducing their output. The only problem is that the mammalian brain is very energy hungry and requires a lot of ATP to remain functional.

The ‘Diving Reflex’ is observed when diving past the aerobic diving limit. This reflex includes the slowing of the heart rate (bradycardia) and regional vasoconstriction to produce metabolic depression.

The Diving Reflex

The bradycardia seen in the diving reflex, reduces the heart rate from around 60-70 to 5-10 beats per minute. This is combined with regional vasoconstriction to increase the length of dives. The regional vasoconstriction is seen across the body except the brain as it would be unable to survive any reduction in blood flow. The amount by which blood flow is reduced across the rest of the body varies from 80-95%. This essential sets up a near closed blood flow from the lungs, to the heart, to the brain. Blood flow from the heart to the rest of the body is minimal.

Bradycardia prevents a change in stroke volume, blood pressure and blood flow, which if altered may damage the body. So even though the dimensions of the cardiovascular system have been reduced, the blood flows around the ‘closed circuit’ of the heart, lungs and brain as it would flow round the complete cardiovascular system under aerobic conditions.

The ‘closed circuit’ is able to remain aerobic from oxygen stores in the blood, muscles and lungs. The rest of the body remains aerobic only for as long as the oxygen bound to the myoglobin of the muscles lasts, barely any oxygen is received from the blood or lungs due to the extreme vasoconstriction. This means the rest of the body becomes anaerobic much faster than the ‘closed circuit’, the anaerobic respiration results in production of lactate.

Because of this, high levels of lactate are observed in the muscles, whereas levels are low in heart, lung and brain. Lactate produced by anaerobic respiration of the rest of the body is stored in the muscles until resurfacing. Lactate remains in the muscles due to the regional vasoconstriction, which essentially has disconnected them from the blood flow.

Upon resurfacing, regional vasoconstriction and bradycardia cease. This results in a ‘Wash out’ of lactate. All the lactate stored in the muscles during the dive is released into the bloodstream, thus increasing blood lactate levels. The lactate is metabolised however, in the presence of oxygen. The lactate produced during the dive must be metabolised before another anaerobic dive may occur. Therefore the longer the dive, the longer it takes before another dive may occur. The period of time between dives spent metabolising lactate, is known as the recovery period. Because of this, long dives are not desirable (unless necessary, such as escaping a predator) as it means less time can be spent beneath the water.

Energy Saving Behaviour

To further preserve energy, diving mammals will perform diving locomotion which reduces muscle energy requirements as much as possible. Diving mammals will use a combination of actively stroking for propulsion and gliding to preserve energy. Typically the descent of a dive requires stroking (combined with brief glides) to reach large depths due to buoyancy of the animal. The ascent however consists almost completely of long gliding behaviour in an attempt to expend as little energy as possible. Stroking it is not needed due to buoyancy, which causes the animal to rise to the surface.

Another energy saving behaviour is the induction of voluntary hypothermia. Whilst diving, mammals actively seek cooler waters, as a decrease in temperature causes a decrease in metabolic rate. If the animal is able to decrease their metabolic rate, the length of the dive can be extended.

Hydrostatic Pressure

Pressure can be measured in terms of atmospheres. At sea level (0m), pressure is the equivalent of 1 atmosphere or 1atm.Underwater, the pressure increases by 1atm per 10 meters, therefore at 10 meters below sea level, the pressure is 2atms. At 100 meters below sea level, the pressure rises to 11atms.

Boyle’s law states that pressure multiplied by volume equals a constant value (at a constant temperature) or PV= Constant. This means, if pressure increases, volume decreases (and vice versa). This is important because the body contains many gas filled spaces such as the lungs. Gas is easy to compress, and so as pressure increases (i.e. As we travel deeper into the ocean) the volume of these gas filled spaces within the body decrease in volume.

In order to understand the changes of the body with pressure, there are two other important pressure laws, these are:

Dalton’s Law – The total pressure of a gas constitutes all of the partial pressures within the gas. For example, the total pressure of air at sea level (or Ptot) = 1atm. This means all partial pressures of gases within air must total to 1atm. PN2 (or the partial pressure of nitrogen) = 0.78atm and PO2 = 0.21atm therefore the partial pressures of all the other gases in air must equal 0.01atm.

Henry’s Law – The solubility of a gas in a liquid is proportional to the partial pressure of the gas (above the liquid). This means that if the PN2 in the lungs increases, the amount of nitrogen which dissolves into the blood also increases.

Problems Associated with Hydrostatic Pressure

The main concerns of hydrostatic pressure are; the toxicity of the gases, decompression sickness and barotrauma. The potential of damage being caused by these factors increases as hydrostatic pressure increases.

At certain depths, nitrogen and oxygen can become toxic. At around 20m depth nitrogen can begin to have affect consciousness – altering perception. At around 50m oxygen can cause damage to the central nervous system, lungs and eyes.

Barotrauma is physical damage as a result of pressure. Gas filled spaces are prone to such damage. Major targets of barotrauma are the thorax and the trachea, if the trachea is not strengthened at great depths, the high pressure can cause the trachea to collapse. This is similar with the thorax, as pressure increases, the size of the lungs decreases. At a depth of 40m the lungs are 1/5 of their size at sea level. Such a large decrease in size could cause damage to thoracic muscles. By having a strengthened trachea, elastic diaphragm and strong sternum, it is possible to prevent such damage.

Decompression Sickness

Decompression sickness occurs due to resurfacing too quickly, this is a result of how pressure of nitrogen changes within the body at depth:

Pre-dive

PN2 (0.8atm) is equilibrated between the lungs blood and tissues.

Dive to 30 meters (Compression)

Ptot has increased to 4atms. Due to Dalton’s law, PN2=3.2atms. Due to Boyle’s law, the volume of the lungs has decreased.

PN2 in the lungs quickly reaches 3.2atms, due to their compression. PN2 in the blood slowly equilibrates followed by the tissues. Eventually lungs, blood and tissues have all equilibrated to PN2=3.2atms.

Resurfacing (Decompression)

Resurfacing too quickly means PN2 in the blood and tissues remains at a value near 3.2atms as there was not a chance to equilibrate with the lungs. At the surface, PN2=0.8atms in the lungs, whilst blood and tissues PN2 still equals 3.2atms. This results in a rapid release in pressure resulting in the formation of bubbles in the blood. The bubbles consist of nitrogen at a partial pressure of 0.8atms and so it is energetically favourable for any remaining dissolved nitrogen to diffuse into these bubbles. Because of this, the bubbles can quickly grow in size.

Decompression sickness arises due to any rapid change in pressure (not just changes in pressure when diving). It is also known as either ‘Caisson’s Disease’ or the ‘Bends’. The only treatment available is to contain the sufferer in a hyperbaric chamber – a chamber where pressure can be controlled and allowed to rise steadily, preventing further formation of nitrogenous bubbles in the blood.

Decompression sickness can arise due to the rapid resurfacing from large depths underwater, this results in a large gradient of partial pressures between the blood, lungs and tissues. The offloading of nitrogen from the blood into the lungs is a relatively slow process and therefore takes time. By resurfacing too fast, the pressure is quickly released causing gases (nitrogen) to go out of solution. This results in the formation of nitrogen bubbles in the blood. The bubbles can join together to become larger and more dangerous, whilst nitrogen is able to diffuse in, further increasing the size. It is energetically favourable for nitrogen to diffuse into the bubbles as they are at normal atmospheric pressure. If decompression sickness reaches the spinal cord, it can result in paralysis.

Avoiding Decompression Sickness

There are basically two ways to combat decompression sickness; limit the load of nitrogen into the body and prevent its distribution. To limit the load of nitrogen, diving mammals have evolved specialised alveoli.

An alveolus consists of a sac-like, bulbous area (where gas exchange takes place) and a terminal bronchiole (a tube connecting to the alveolus where no gas exchange takes place). In terrestrial mammals, pressure (such as that experienced whilst diving) causes the bronchiole to collapse, trapping nitrogen within the bulbous end of the alveoli. With nowhere to go, the nitrogen moves out into the tissues and blood (increasing nitrogen load and the possibility of decompression sickness).

The bronchioles of diving mammals on the other hand consist of strengthened cartilage, preventing them from collapse. Under pressure it is the alveoli which compresses first. Nitrogen in the alveolus moves out into the bronchiole. As no gas exchange occurs in the bronchiole, nitrogen is not able to move into the surrounding blood and tissues. Nitrogen load is therefore decreased as is the possibility of suffering from decompression sickness upon resurfacing. Such alveolar collapse occurs at a depth of 30m in Weddell seals, meaning the partial pressure of nitrogen in the tissues does not increase further than 3.2atms.

The other method of avoiding decompression sickness is to limit the distribution of nitrogen. This is done by peripheral vasoconstriction. As with oxygen limited dives that extend past the aerobic diving limit, regional or peripheral vasoconstriction result in decreased blood flow to the body. Blood flow is only preserved to the lungs, heart and brain. The benefit of this is that fatty tissue (i.e. the areas to where blood flow is restricted) has high nitrogen solubility, so reducing the blood flow to these areas also reduces the amount of nitrogen able to dissolve into the tissue. The brain on the other hand consists mainly of watery tissue which has much lower nitrogen solubility; it also offloads nitrogen much faster and therefore has a reduced risk of bubble growth.

Opioid Analgesics (Morphine) & Equine Colic (Butorphanol)

Introduction

The primary effect of opioids is to temporarily remove pain when used at therapeutic levels; this is done by binding to opioid receptors found primarily in the central nervous system (some receptors are found in the gastrointestinal tract). When larger doses are given, opioids can induce beneficial and non-beneficial pharmacological effects such as sedation, respiratory depression or constipation. The term given to non-synthetic opioids is opiates; opiates are derived from the naturally occurring opium alkaloids found in the resin of the opium poppy.

The main uses of opioids include:

  • Treatment of acute pain (e.g. post-operative)
  • Palliative care to alleviate serve chronic pain (e.g. cancer)
  • Surgical premedication regimes (due to their calming, sedative action – also reduces the amount of post pain relief required)
  • Neuroleptanalgesia (a state of quiescence, altered awareness, and analgesia produced by a combination of an opioid analgesic and a neuroleptic – a tranquilliser). And neuroleptanaesthesia (a form of anaesthesia achieved by the administration of a neuroleptic agent, a narcotic analgesic, and nitrous oxide with oxygen. Induction of anaesthesia is slow, but consciousness returns quickly after the inhalation of nitrous oxide is stopped)
  • Restraint
  • Antitussive (the alleviating or suppressing coughing)

Pharmacology

The body naturally releases endogenous opioid peptides or endorphins which bind to opioid receptors in the body. There are three primary receptor types, each with different functional responses and these are:

  • μ (mu) – Responsible for supraspinal (above the spine) analgesia, respiratory depression, euphoria and physical dependence of opioids (misuse and abuse of opioids)
  • κ (kappa) – Responsible for spinal analgesia, miosis (pupil constriction of the eye) and sedation
  • δ (delta) – Responsible for hallucinations and dysphoria (agitation and anxiety)

Exogenous opioids (synthetic or natural) mimic the body’s own endogenous opioids and are therefore able to bind to the above receptors – resulting in a response specific to the receptor they bound.  Opioids are able to either stimulate or depress the receptors, meaning opioid drugs can be classes as; agonists, antagonists or both – agonists-antagonists. Agonists bind to receptors and induce pharmacological responses whereas antagonists bind to receptors and do not produce a response, this makes them able to counteract the effect of other drugs or endogenous compounds.

Agonists are used for the primary reasons listed earlier, mainly analgesia. Examples of opioid agonists are:

  • Morphine
  • Pethidine
  • Methadone
  • Fentanyl
  • Etorphine.

Antagonists are primarily used to reverse the effects of agonists i.e. analgesia. They do this by binding to μ and κ opioid receptors, which together are responsible for analgesia. Examples of opioid antagonists include:

  • Naloxone (Narcan)

Agonists-Antagonists have both agonistic and antagonistic properties. This means they are able to antagonise the pure agonists (e.g. morphine) at μ and κ opioid receptors but they also have their own milder agonistic effects. The agonist effect is sufficient enough to be used as analgesics. Examples of opioid agonists-antagonists include:

  • Butorphanol
  • Pentazocine (Fortral)
  • Nalorphine
  • Diprenorphine (Revivon)
  • Buprenorphine (Temgesic)

The principal usage of opioids in medication is for analgesia. Analgesia is the loss of pain perception. Opioids effect both the physical and psychological perception of pain, physically blocking or raising the threshold of pain stimulation and removing the association of pain with fear. Associated with analgesia is sedation which is not considered hazardous, respiratory depression (which can also be associated with opioid analgesia) however can be a distressing side effect. A list of unwanted opioid effects includes:

  • Sedation
  • Excitement
  • Respiratory depression
  • Cough suppression
  • Nausea
  • Vomiting
  • Constipation

Opioid Selection

There are many opioids available for use, each with different properties, when selecting an opioid it is important to consider its potency, how quickly it acts (speed of onset) and how long it lasts (duration). The best analgesics are those which have a mild potency, rapid onset and a long duration of effect. When combining an opioid with a neuroleptic for neuroleptanalgesia, the desired properties of the opioid are slightly different; strong potency, rapid onset and brief period of duration.

As opioids can have an effect on the gastrointestinal system, (as opioid receptors are also found in the gastrointestinal tract) if they are to be given orally then they must have low lipid solubility.

Another point to consider is whether to use an agonist or an agonist-antagonist as both are able to produce analgesia. The main consideration is that pure agonists are more reliable and predictable than agonist-antagonists, but the agonist-antagonists produce fewer side effects such as vomiting, sedation and respiratory depression. Also as agonist-antagonists have antagonistic effects, any further use of analgesics may be compromised.

Below is a comparison of the potency of certain opioids relative to morphine, the most potent being Etorphine. Etorphine (or Immobilon) is extremely powerful and typically only used to immobilise large mammals (e.g. elephants). Due to its potency it can prove lethal to man.

Drug Relative Potency
Meperidine 0.1
Morphine 1
Butorphanol 1-2
Hydromorphone 10
Alfentanil 10-25
Fentanyl 75-125
Remifentanil 250
Sufentanil 500-1,000
Etorphine 1,000-3,000

Opioids are often used as part of a pre-medication routine i.e. before surgery as a pre-emptive form of analgesia. This is because once pain has been established (i.e. during surgery) pain relief drugs prove less effective. As a result larger doses would be needed to prevent the pain which increases the onset of associated side effects e.g. respiratory depression.

Examples of Opioids and their Properties:

Morphine

Morphine (agonist) is considered the standard opioid with all other forms of analgesia being compared against it. It is the most potent natural analgesic, more potent derivatives have been artificial synthesised. Morphine produces a mixture of stimulant and depressant actions depending on the size of the dose as well as the species and absence or presence of pain.

Differences between the species can be observed e.g. in the dog, the cortex is depressed and little excitement is produced. In the cat, very small doses are able to induce excitement and in the horse morphine will not produce excitement if no pain is present (effect is less predictable in horses however). Despite this morphine is safe to use in all species as long as the correct dosage is used, the presence of excitement tends to increase with dose.

The duration of morphine is about 4 hours in all species, it is eventually metabolised by the liver. It is normally injected subcutaneously at a dose of around 0.1mg/Kg (in dogs and cats).

Use of morphine can either stimulate the medulla (which is followed by depression of the medulla) or directly depress the medulla.

Morphine has a number of effects on the gastrointestinal tract. Initially it may invoke vomiting and defaecation which is followed by constipation. Constipation is due to local effects on the small/large intestinal opioid receptors. Segmental tone of the intestines increases, along with sphincter tone but the action peristalsis decreases. This increases the time taken for intestinal contents to pass.

Other areas affected by morphine include:

  • The chemoreceptor trigger zone (CTZ) of the medulla is stimulated by morphine – this induced vomiting.
  • The occulomotor centre is stimulated which is responsible for producing miosis.
  • The cough centre is depressed – reducing coughing but making post-operation mucus accumulation a possible problem.
  • The vagal centre is stimulated, which increases gastrointestinal activity and is responsible for the initial defaecation. If a large dose is administered bradycardia may be induced (slowed heart rate <60bpm) by myocardium depression.
  • The respiratory centre is easily depressed by morphine, even with a low dose. This is due to a reduced response to elevated CO2 levels. The mechanisms involved in the regulation of respiratory rhythm are also affected – contributing to the overall depression of the respiratory centre.

Butorphanol

Butorphanol (agonist-antagonist) is a widely used sedative and analgesic in dogs, cats and horses – combined with tranquillisers for sedation. It is around 1-2 times as potent as morphine, but it does have a slightly shorter duration of action at around 2-3 hours (Morphine – 4 hours). It has a much less profound effect on the respiratory system as the dose increases compared to morphine.

One major use of Butorphanol is for intravenous administration in the horse (0.1mg/Kg) to alleviate abdominal pain associated with torsion, impaction, intussusception (intestinal prolapse) and spasmodic colic.

Equine Colic

The term colic can encompass all forms of gastrointestinal conditions which cause pain as well as other causes of abdominal pain not involving the gastrointestinal tract. Some examples are:

  • Spasmodic colic – Increased peristaltic contraction
  • Impactive colic – Caused by irritation to the lining of the bowel or ileum due to diet or ingestion of large amounts of sand/ dirt
  • Obstructive colic – Obstruction of the bowel by large food masses
  • Flatulent colic – Build of intestinal gases causing distension and pain
  • Parasitic colic – Intestinal pain from parasites such as roundworm or tapeworm
  • Idiopathic colic – From another cause which remains unknown

There are also many diagnostic tests for equine colic:

  • Increased heart rate with decreased circulating volume
  • Distinctive behavioural signs
  • Auscultation – Listening to internal body sounds
  • Abdominocentesis – The extraction of fluid from the peritoneum which can be useful in assessing the state of the intestines
  • Nasogastric Intubation – Insertion of a tube from the nose to the stomach which can be used to drain excess liquid from the stomach – for therapeutic reasons and for diagnosis
  • Rectal/Faecal examination

There are also many drugs/treatments available to treat the symptoms:

  • Analgesics
  • Spasmolytics
  • Lubricants/laxatives
  • Antizymotics – Used against disease producing organisms e.g. bacteria
  • Anthelmintics – Used against parasites
  • Fluid therapy

The major analgesics used against colic are α2-agonists (xylazine, romifidine and detomidine), opioids (butorphanol) and NSAIDs (flunixin).

Butorphanol is usually used alongside small doses of xylazine, romifidine and detomidine. This is because it has minimal effects on the cardiovascular system (which is not true for xylazine, romifidine and detomidine). Both butorphanol and the α2-agonists have a duration of around 2-3 hours and they both reduce intestinal motility/activity.