Author Archives: Pat Neligan

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About Pat Neligan

Pat Neligan lives and works in Galway, Ireland

Common Questions Regarding Stewart Approach to Acid Base Chemistry

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I receive a lot of emails from confused doctors regarding the modern (Stewart) approach to acid base chemistry.

A common question relates to the relative quantity of hydrogen/hydronium and hydroxyl ions. For example, if chloride is dissolved in water there is a net increase in hydrogen and a net decrease in hydroxyl. Where does the hydroxyl go?

Another question is: why if the pH of NaCl 0.9% solution 5.5 when the SID (Strong Ion Difference) is 0? Finally everyone is confused about contraction alkalosis and dilutional acidosis.

This post will attempt to explain these phenomena. I make no attempt here to explain the basics of acid base chemistry. For this read my chapters in Miller’s Textbook of Anesthesia or Longnecker’s Anesthesiology.

Acids versus Bases

Stewart utilized the Arrhenius theory of acid base: you put chloride into water, water dissociation changes to maintain electrical neutrality releasing hydrogen ions and the solution becomes acidic. In this way chloride delivers a hydrogen ion to the solution and Chloride is an acid. This may appear confusing (where does the OH– go if H+ is delivered to the solution), but if you read below, the answer is really simple. Stewart’s approach is entirely consistent with Bronsted-Lowry, but heavily emphasizes strong ions and weak anions as the independent variables. Water is a dependent variable, as is HCO3–.

It is best to describe water as an amphiprotic molecule – simply it can be an acid or a base – a proton donor or a proton acceptor. H2O (acid)  + H2O (base) ≤-≥ H3O+ + OH–

The tendency for water to dissociate into its component parts is governed by the Kw’ – the autoproteolysis constant for water:

Kw = (H3O+ ) a(OH–)

So water can act as an acid or a base depending on what is dissolved in it. We tend to get a little hung up on which is the acid and which is the base depending on how you look at it: in our teaching Chloride is functionally an acid. A lot of people think it is a base. The following my clarify your thinking:

An example – if HCl is dissolved in water:

HCl + H2O <->  H3O+ + Cl–

In this situation water acts as a conjugate base – a proton acceptor. Note that there is no net generation of OH– as the proton donor was Chloride.Likewise, if you dissolve NaOH into water

NaOH + H2O <->  Na+ +H2O + OH–

So water in this situation acts a conjugate acid, a proton donor – the conjugate acid of a strong base. Whenever, in physiology, you have a strong anion you have a conjugate acid (Hn+); whenever you have a strong cation, you have a conjugate base (OH‑). In mass conservation, each time you lose a Cl- you lose its accompanying Hn+. What Stewart emphasizes is that it is not the loss of the proton that is the problem – the supply is potentially unlimited, it is the loss of the electrolyte.  The major teaching point in Stewart is that NaCl is not Na+ + Cl– (in other words the charge on sodium is balanced by the charge on chloride) rather it is NaOH + HCl.

Remember the pKa = pH + pOH

Now, if you come along and make up a solution of NaOH + HCl + H2O (normal saline), what happens?

NaOH + HCl + H2O <-> Na+ + OH– + H3O+ + Cl–

But it is not a simple as that – because HCl is a much stronger acid than NaOH is a strong base.  Hence, due to their differing pKas, HCl generates more H+ than NaOH generates OH– (it has a steeper titration curve). The result, in a bag of fluid is a pH of 5.5. However, the SID is 0 – so I don’t know if the differing titration curves for HCl versus NaOH contributes somewhat to the acidifying effect of NaCl.

This last point is important – even if charges are balanced, there may be different amounts of hydrogen and hydroxyl ions present due to the pKa of the various acids and bases.

I hope this resolves the confusion: putting chloride into a solution of water does not lead to the mysterious disappearance of OH‑. Strong ions never, ever, exist without something to balance the charge; a conjugate acid or base. Functionally H+ is actually added, but it is stirred into the aqueous stew.

Dilutional acidosis and contraction alkalosis

t is important to remember that the Stewart approach emphasizes that pH is dependent on: SID (strong ion difference), pCO2 and Atot (total weak acid-anion concentration). The assumption when one looks at changes in SID is that there are no concomitant changes in the other variables (of course there is – we may hyperventilate or hypoventilate to correct the pH) – for illustrative purposes. So, under normal circumstances, the SID is 44 mEq/L. That means that there is 44mEq/L of buffer base or weak anions (Atot) balancing the charge – phosphate, bicarbonate and protein (principally albumin) – table 2 below. It is assumed the Atot  remains stable. An increase in SID – as a result of contraction – immediately induces a base excess that must be associated with an increase in OH–. This does not imply that hyroxyl ions appear and hydrogen ions disappear – they were always there – but in different concentrations. The same is the case if the system is diluted – adding free water and keeping Atot stable induces an acidosis by reducing SID.

For example: construct a liquid that starts with 15 liters of water and add 2.1M of NaOH (140mmol/l) of NaOH and 1.5M of HCl (100mmol/L). This is obviously a highly alkaline solution as there is an excess of 40mmol/L of OH– (40mmol). If you add 3 liters of water to this the concentration of Na+ falls to 116mmol/L (that is 116mmol/L of OH–), and the concentration of Cl– falls to 83mmol/l (that is the 83mmol/L of H+). The total amount of excess OH– over H+ has reduced – so the pH must fall.

In physiology, the 40mEq/L SID is represented by weak acids (Atot), and, other things being equal, these do not change. These are represented by A – and carry, functionally, 40mEqL of H+. So, if you do your mathematics – the total H+ concentration is 83 + 40mEq/L (123) wheras the total OH– conventration is 116mmol/L – a difference of 7.

In effect, there is a net gain of 7mEq/L of HnO+/H+,  and this results in metabolic acidosis.

 

Table 1

ECF volume

 ECF State

[Na+]

[Cl–]

[OH–]*

SID

[Atot–]*

pH
 

15000

 Normal

140

100

40

40

40

7.4
add water

18000

 Expanded

116

83

33

33

40

<7.3
remove water

13000

 Reduced

161

115

46

46

40

>7.5

*Atot=OH under normal circumstances; in this illustration Atot is kept stable.

Of course, this would result in devastating acidosis if it occurred in a human. Consequently four things occur to balance this 1. K+translocates from the intracellular space. 2. Albumin also becomes diluted (ICU alkalosis). 3. HCO3– combines with the now abundant H+ ions forming carbonic acid. 4. CO2 is blown off due to a fall in the pH of CSF.

On the face of it, this would appear to be the classic approach to ABB – but it is not. The classic approach suggests that the fall in HCO3– is due to dilution, in the Stewart approach the fall is due to consumption – as a buffer. Inevitably, as the negative charge carried by HCO3– falls, there is a dual effect – yes it represents buffering, but the charge differential between SID and Atot (buffer base or weak acids) falls, and the pH normalizes.

Does the HCO3– become diluted just like NaCL? Maybe, I’m not sure:  remember HCO3– is part of a different control system. Also, as the pH falls, being weak acids, the acidic effect of bicarbonate, albumin and phosphate increases.

Table 2: Buffer Base
Buffer Base Plasma (Atot) Buffer Base Whole Blood (Atot)
HCO3 24mEq/L

PO4 1 mEq/L

Albumin 17mEq/L

 HCO3 20mEq/L

PO4 0.5mEq/L

Albumin 9.5mEq/L

Hemoglobin 18mEq/L

What about contraction alkalosis? Take our 15L ECF and remove 2L of water – no change in quantity of Na, Cl or the concentration of buffer base (weak acid).  The sodium concentration increases to 161mEq/L (OH- is the same); the chloride concentration increases to 115mEq/L. The SID is now 46mEq/L. Other things being equal the BB/Atot is 40mEq/L – so there is now an excess of 6mEq/L of OH– compared with before: metabolic alkalosis. 
Interestingly, universally, the HCO3– increases by a more or less similar amount. This is where Stewart’s original work is really weak – why? Either we generate more bicarbonate due to hypoventilation – slow – or else the bicarbonate becomes concentrated like everything else. Whatever way you look at it, the increasing bicarbonate functionally buffers the alkalosis (it being a weak acid – an anion).

There are lots of potential in vitro lab or in vivo animal studies that could be carried out to actually iron out exactly what goes on. I would imagine that if you took an animal, tied off the renal arteries, put in an arterial line – administered a load of water and checked the full spectrum of labs before and after you could once and for all answer this question.

I have found, over the years, that the most comfortable place to sit is in between the extremes of the Stewart and traditional approaches. I believe that Stewart was wrong about bicarbonate – it is far more important that he gave credit for, and while not a component of SID – and probably not an independent variable, it is a major player in acid base chemistry.

Is there a pool of hydrogen and hydroxyl ions that appear and disappear depending on the SID, Atot and pCO2? Yes of course there is – water exists as big blobs that exhibit either a positive or negative charge (HnO+ or HOn–). The totality of charge exhibited depends on the milieu – but really it is charge that is added alongside electrolytes – NaOH, for example. In addition, alterations in charge of weak acids resulting from changes in pH is probably more important than currently recognized (in other words Atot becomes more acidic with acid and less acidic with alkali – due to the proximity of pKa to pH 7.4 – more acidic more ionized, less acidic less ionized).

This article is entirely the work of Patrick Neligan MB FCAI FJFICM. It is not to be reproduced without permission. It is for educational purposes only. © PJN 2011

Vasopressors for Hypotension During Cesarean Delivery Under Spinal Anesthesia

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Anesth Analg. 2012 Feb;114(2):377-90

Vasopressor use during neuraxial anaesthesia/analgesia is more prevalent today than ever before. It is my impression that phenylephrine has emerged as the defacto pressor of choice over the past decade.  However, in 2001 95% of consultant anaesthetists used ephedrine exclusively (Burns Anaesthesia 2001). What has changed over that decade? A series of studies that have suggested that phenylephrine has certain haemodynamic advantages over ephedrine.  In particular the appearance of increased acidosis in babies of mothers that have received ephedrine (this may not be clinically significant) has tilted therapy towards phenylephrine. This month’s Anesthesia and Analgesia features a timely systematic review of vasopressor therapy during spinal anaesthesia (SA) for Caesarian Section (CS). I would recommend that every anaesthetist that is involved with obstetrics read and digest Dr Habib’s review.  To whet your appetite, here is a summary of the conclusions.

  1. Phenylephrine is as effective as ephedrine for treating hypotension associated with SA.
  2. Phenylephrine is superior to ephedrine for prevention of intraoperative nausea and vomiting (IONV).
  3. Phenylephrine infusion is superior to phenylephrine boluses for IONV.
  4. Phenylephrine is superior to ephedrine in terms of fetal acid base status – higher umbilical artery pH and lower base deficit.
  5. Phenylephrine may reduce cardiac output, but it is unclear if there is any clinical significance to this.
  6. As one would expect, due to each patient having different blood pressures, different pharmacodynamics and different fluid status – there is no optimal dose of phenylephrine in this setting.

Perioperative Single Dose Ketorolac to Prevent Postoperative Pain

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Anesth Analg. 2012 Feb;114(2):424-33

I have been a sceptic of meta-analyses, for many years. The purpose of these studies is to take a large volume of literature; both published and unpublished, and test hypotheses. The idea is to replicate a large randomized controlled trial by combining many studies together.  Unfortunately, rather than coming up with hundreds of studies involving thousands of patients, invariably the selection criteria excludes a large number of studies, and relatively few are ultimately analyzed. Often no conclusions are reached or the results are refuted by a subsequent large  randomized controlled trial.

This month’s Anesthesia and Analgesia features a  meta-analysis of single dose ketorolac for prevention of postoperative pain. Ketoralac is a NSAID analgesic very similar to diclofenac – but importantly one that can be given by intravenous bolus (I routinely use it in my clinical practice). The analysis included 13 studies, approximately 800 patients: ketorolac versus placebo, for prevention of postoperative pain.

I was surprised to find that the most efficacious dose of ketorolac was 60mg – this dose provided effective opioid sparing analgesia and reduced the incidence of PONV (post operative nausea  and vomiting). Interestingly, intramuscular administration of ketorolac appears to be more effective than intravenous. The authors claimed that the standard dose of ketorolac, 30mg, was essentially ineffective.

Will this study change my clinical practice?

When reading studies such as this you really have to go beyond the abstract. With meta-analyses it is essential to see what question the authors were asking:

“We included only randomized clinical trials of a single perioperative (preoperative or intraoperative) systemic ketorolac with an inactive (placebo or “no treatment”) control group. Included studies had to report at least pain scores or opioid consumption on postoperative pain outcomes.”

Also “Trials evaluating >1 dose of perioperative ketorolac were also excluded to maximize clinical homogeneity. Studies containing a concurrent use of a different analgesic regimen were excluded if a direct comparison of ketorolac and placebo could not be established.”

In other words – if investigators had planned to give more than one dose of ketorolac or were using a multimodal strategy, their studies were excluded. In other words – my clinical practice was excluded.

The accompanying editorial, from Henrik Kehlet’s group makes several criticisms of the study (Click here) and is reassuring to those of us who use ketorolac in multimodal regimes. They systematically review the literature that includes ketorolac, clearly demonstrating efficacy of the 30mg dose. They also, and very helpfully, demonstrate that ketorolac has minimal association with postoperative complications.

What I learned from this paper:  single low dose NSAID is inadequate for postoperative pain relief.

Perioperative Visual Loss

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Nothing terrifies an anaesthetist as much as the prospect of a patient waking up blind. It happens, but very infrequently. Who is at risk? What surgeries? What are the risk factors? Is there anything we can do to prevent and treat visual loss?

Perioperartive visual loss is associated with posterior ischemic optic neuropathy (ION), anterior ION, and central retinal artery occlusion (CRAO).

In the February 2012 issue of Anesthesiology (click here), the ASA has issued a practice advisory for the prevention of preoperative visual loss. Below is a summary of the article.

1. Preoperative Patient Evaluation and Preparation

  • There are no clear preoperative patient characteristics that predispose patients to perioperative ION.
  • However – prolonged procedures, particularly with the head elevated, with substantial blood loss (44.7%) appears to identify high risk patients. Spine surgery in the prone position that goes on for several hours (>6.5 hours) appears to be the highest risk operation.
    • So Risks:
      • Anaemia
      • Large volume blood loss
      • Prolonged surgery
      • Prolonged surgery with significant blood loss.
      • There is no evidence that an ophthalmic or neuro-ophthalmic evaluation would be useful in identifying patients at risk for perioperative visual loss (PVL).
      • Anaesthetists should consider informing patients in whom prolonged procedures, substantial blood loss, or both are anticipated that there is a small, unpredictable risk of perioperative visual loss.
      • Because the frequency of visual loss after spine surgery of short duration is very low, it is probably unnecessary to inform all spine surgery patients of this risk.

2. Intraoperative Management

Blood Pressure Management

  • Systemic blood pressure should be monitored continually in high-risk patients.
  • The use of deliberate hypotensive techniques during spine surgery has not been shown to be associated with the development of  PVL (perioperative visual loss).
  • The use of deliberate hypotension for these patients should be determined on a case-by-case basis.
  • Blood pressure should be maintained within 24% of baseline, and the systolic blood pressure should not fall below 84mmHg. In addition, extreme care should be taken with patients that have chronic hypertension.

Management of Intraoperative Fluids

  • Central venous pressure monitoring should be considered in high-risk patients (I disagree with this recommendation as I believe that there is no evidence that CVP is an accurate measure of blood volume or anything else for that matter).
  • Colloids should be used along with crystalloids to maintain intravascular volume in patients who have substantial blood loss.

Management of Anemia

  • Haemoglobin values should be monitored periodically during surgery in high-risk patients who experience substantial blood loss.
  • However, there is no documented lower limit of hemoglobin concentration that has been associated with the development of perioperative visual loss. Experts suggest keeping HgB >9.4g/dL.
  • Thus there is no clear transfusion threshold to prevent PVL.

Use of Vasopressors

  • There is insufficient evidence to provide guidance for the use of α-adrenergic agonists in high-risk patients during spine surgery. There is concern that prolonged use of vasopressors may precipitate optic nerve ischaemia (although I don’t believe that there is any published evidence on this point).

Patient Positioning

  • Prone positioned patients often emerge with significant facial oedema. There is no pathophysiologic mechanism by which facial oedema can cause perioperative ION.
  • There is no evidence that ocular compression causes isolated perioperative anterior ION or posterior ION.
  • Direct pressure on the eye should be avoided to prevent CRAO.
  • The high-risk patient should be positioned so that the head is level with or higher than the heart when possible.
  • The high-risk patient’s head should be maintained in a neutral forward position (e.g., without significant neck flexion, extension, lateral flexion, or rotation) when possible.

3. Staging of Surgical Procedures

  • Staged spine surgery procedures may decrease the risk of PVL in some patients and should be considered.

4. Postoperative Management

  • A high-risk patient’s vision should be assessed when the patient becomes alert (e.g., in the recovery room, intensive care unit, or ward).
  • If there is concern regarding potential visual loss, an urgent ophthalmologic consultation should be obtained to determine its cause.
  • Additional management may include optimizing blood pressure, haemoglobin and oxyhaemoglobin saturation.
  • To rule out intracranial causes of visual loss, consider magnetic resonance imaging.
  • There is no role for antiplatelet agents, steroids, or intraocular pressure-lowering agents in the treatment of perioperative PVL.

ASA Periopeative Pain Guidelines

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The ASA has issued guidelines for acute pain management in the perioperative setting. Click on this link to read guidelines. Obviously there is a North American flavour to these guidelines, but they are generalisable.

Summary:

1. Institutional Policies and Procedures for Providing Perioperative Pain Management

  • Anaesthetists offering perioperative analgesia services should provide ongoing education and training to ensure that hospital personnel are knowledgeable and skilled with regard to the effective and safe use of the available treatment options within the institution.
  • Educational content should range from basic bedside pain assessment to sophisticated pain management techniques (e.g., epidural analgesia, PCA, and various regional anesthesia techniques) and non-pharmacologic techniques (e.g., relaxation, imagery, hypnotic methods – these are US guidelines!).
  • For optimal pain management, ongoing education and training are essential for new personnel, to maintain skills, and whenever therapeutic approaches are modified.
  • Anaesthetists and other healthcare providers should use standardized, validated instruments to facilitate the regular evaluation and documentation of pain intensity, the effects of pain therapy, and side effects caused by the therapy.
  • Anaesthetists responsible for perioperative analgesia should be available at all times to consult with ward nurses, surgeons, or other involved physicians.
  • They should assist in evaluating patients who are experiencing problems with any aspect of perioperative pain relief.
  • Anaesthetists providing perioperative analgesia services should do so within the framework of an Acute Pain Service.
  • They should participate in developing standardized institutional policies and procedures.

2. Preoperative Evaluation of the Patient

  • A directed pain history, a directed physical examination, and a pain control plan should be included in the anaesthetic preoperative evaluation.

3. Preoperative Preparation of the Patient

  • Patient preparation for perioperative pain management should include appropriate adjustments or continuation of medications to avert an abstinence syndrome, treatment of preexistent pain, or preoperative initiation of therapy for postoperative pain management.
  • Anaesthetists offering perioperative analgesia services should provide, in collaboration with others as appropriate, patient and family education regarding their important roles in achieving comfort, reporting pain, and in proper use of the recommended analgesic methods.
  • Common misconceptions that overestimate the risk of adverse effects and addiction should be dispelled.
  • Patient education for optimal use of PCA and other sophisticated methods, such as patient-controlled epidural analgesia, might include discussion of these analgesic methods at the time of the preanaesthetic evaluation, brochures and videotapes to educate patients about therapeutic options, and discussion at the bedside during postoperative visits.
  • Such education may also include instruction in behavioral modalities for control of pain and anxiety.

4. Perioperative Techniques for Pain Management

  • Anaesthetists who manage perioperative pain should use therapeutic options such as epidural or intrathecal opioids, systemic opioid PCA, and regional techniques after thoughtfully considering the risks and benefits for the individual patient.
  • These modalities should be used in preference to intramuscular opioids ordered “as needed.”
  • The therapy selected should reflect the individual anesthesiologist’s expertise, as well as the capacity for safe application of the modality in each practice setting.
  • This capacity includes the ability to recognize and treat adverse effects that emerge after initiation of therapy.
  • Special caution should be taken when continuous infusion modalities are used because drug accumulation may contribute to adverse events.

5. Multimodal Analgesia

  • Whenever possible, anaesthetists should use multimodal pain management therapy.
  • Unless contraindicated, patients should receive an around-the-clock regimen of NSAIDs or paracetamol.
  • Regional blockade with local anaesthetics should be considered.
  • Dosing regimens should be administered to optimize efficacy while minimizing the risk of adverse events.
  • The choice of medication, dose, route, and duration of therapy should be individualized.

6. Patient Subpopulations

Paediatric patients

  • Aggressive and proactive pain management is necessary to overcome the historic under-treatment of pain in children.
  • Perioperative care for children undergoing painful procedures or surgery requires developmentally appropriate pain assessment and therapy.
  • Analgesic therapy should depend upon age, weight, and comorbidity, and unless contraindicated should involve a multimodal approach.
  • Behavioral techniques, especially important in addressing the emotional component of pain, should be applied whenever feasible.
  • Sedative, analgesic, and local anaesthetics are all important components of appropriate analgesic regimens for painful procedures.
  • Because many analgesic medications are synergistic with sedating agents, it is imperative that appropriate monitoring be used during the procedure and recovery.

Geriatric patients

  • Pain assessment and therapy should be integrated into the perioperative care of geriatric patients.
  • Pain assessment tools appropriate to a patient’s cognitive abilities should be used. Extensive and proactive evaluation and questioning may be necessary to overcome barriers that hinder communication regarding unrelieved pain.
  • Anaesthetists should recognize that geriatric patients may respond differently than younger patients to pain and analgesic medications, often because of comorbidity.
  • Vigilant dose titration is necessary to ensure adequate treatment while avoiding adverse effects such as somnolence in this vulnerable group, who are often taking other medications (including alternative and complementary agents).

Other subpopulations

  • Anaesthetists should recognize that patients who are critically ill, cognitively impaired, or have communication difficulties may require additional interventions to ensure optimal perioperative pain.management.
  • Anaesthetists should consider a therapeutic trial of an analgesic in patients with increased blood pressure and heart rate or agitated behavior when causes other than pain have been excluded.

Local Anaesthesia Toxicity (tutorial)

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Patrick Neligan, Consultant in Anaesthesia & Intensive Care, Galway University Hospitals (c)

Clinical Scenario

A 37 year old female undergoes bilateral mammoplasty. The procedure is performed under general anaesthesia. Prior to incision the wound was infiltrated with 20ml of 1% lignocaine, on each side. Intraoperatively the patient’s temperature was 37.5 degrees celcius, heart rate was 100 to 120 beats/min and blood pressure was 100/50. Prior to extubation, the surgeon injects 5ml of lignocaine 1% subcutaneously into each breast.

Neuromuscular blockade is reversed with neostigmine and glycopyrrolate and the patient returned to the recovery on supplemental oxygen.

Following admission to recovery, the patient complains of dizziness, shortness of breath and paraesthesia around the mouth and tongue. Her temperature is 38 degrees celcius, heart rate 106, blood pressure 90/50, respiratory rate 30. She says that she has a choking feeling. Moments later she loses consciousness and has a grand mal seizure.

What is the likely mechanism of injury?

Local anaesthetics are drugs that produce reversible depression of signal conduction along nerve fibers. Depending on the dose and site of application, they cause analgesia, anaesthesia and neuromuscular blockade.

The first local anaesthetic discovered was cocaine. Subsequent synthesis of alternative agents early in the twentieth century were ester derivatives of benzoic acid. These are known as “ester” local anaesthetics. Lignocaine was synthesized in 1943 – an amide derivative of diethylamino acetic acid (“amides”). Most subsequent agents introduced into practice have been amides due to lower associated incidence of side effects (principally anaphylaxis).

Local anaesthetics work by blocking voltage gated sodium channels. They interrupt the influx of sodium into nerve cells, preventing propagation of the action potential.

The agent, a weak base, is injected as hydrochloride salt in an acid solution – tertiary amine group becomes quaternary and suitable for injection (i.e. dissolves in solution). Following injection, the pH increases (due to the higher pH of the tissues, which is usually 7.4) and the drug dissociates, the degree of which depends on pKa, and free base is released. Lipid soluble (because it is uncharged) free base enters the axon. Inside the axon the pH is lower (because the environment is more acidic), and re-ionization takes place (to BH+). The re-ionized portion enters the Na+ channels and blocks them, preventing depolarization.

Figure 1: Mechanism of Action of Local Anaesthetic Agents

Although local anaesthetics are administered to be injected locally there is always associated systemic absorption. Adrenaline is commonly added to the local anaesthetic mixture to induce local vasoconstriction and reduce the absorbed dose. However, if sufficiently large amounts of drug are absorbed, either due to excessive administration or due to inadvertent intravascular injection, complications may ensue. Conversely, lignocaine has been used for decades as an intravenous therapeutic agent in the management of cardiac arrhythmias, and reduction in the adrenergic response to surgical incision.

Local anaesthetics exert toxic effects on the cardiovascular and central nervous system. This became apparent in the late 1970s and early 1980s when a series of patients developed profound cardiovascular depression, in some cases fatal, associated with administration of bupivicaine in high dosage. Bupivicaine, particularly its S-enantiomer, binds irreversibly (covalently) to cardiac conduction tissue – blocking sodium, potassium and calcium channels.

Prior to the development of cardiovascular symptoms and signs, the patient will manifest signs of neurologic toxicity (figure 2). At low levels of toxicity the patient may complain of circumoral numbness, higheadeness and ringing in the ears. These symptoms should alert the clinician to stop the administration of local anaesthetic infusions, through implanted catheters such as epidurals. Increasing toxicity leads to visual disturbances, muscle twitching and convulsions (as in this case). Continued toxicity leads to loss of consciousness, coma, respiratory and cardiac arrest.

Symptoms and signs of CNS toxicity are thought to commence with selective blockade of fast sodium channels in the central nervous system and inhibition of gama-aminobutyric acid (GABA) in cortical cerebral inhibitory pathways. Excitatory neurons appear to be more resistant to local anaesthetics. Consequently, at moderate levels of toxicity (figure 2) there is unopposed activity of these excitatory neurons leading to seizures. With progressive toxicity, there is generalized CNS depression. The occurrence of seizures, then, is an important warning sign of imminent catastrophe.

Local anaesthetics agents, in particular lignocaine, have been used as anti-arrhythmic agents. They produce dose dependent depression of cardiac conduction, by blocking sodium channels. This principally affects sino-atrial and atrio-ventricular nodal conduction. Consequently, the PR interval and duration of the QRS complex is prolonged. Further, as all electrical activity in the heart and vascular smooth muscle is depressed, local anaesthetics have a negative impact on myocardial contractility and cause peripheral vasodilatation. Thus there is a dose dependent fall in cardiac output and blood pressure with inability to compensate. Increasing levels of toxicity may cause severe bradycardia, cardiogenic shock and cardiovascular collapse.

 

What is this cc/cns ratio?

The cardiovascular system is significantly more resistant to the toxic effects of local anaesthetics. Indeed, with moderate CNS toxicity, the increase in excitatory activity may lead to tachycardia and increased cardiac output. However, the onset of convusions is an ominous clinical sign and it is important to anticipate the risk of a devastating cardiovascular event. The cc/cns ratio is the ratio of dosage or blood levels required to produce irreversible cardiovascular collapse to that level required to produce convulsions. The lower the ratio, the more potentially hazardous the drug is. The cardiovascular to CNS ratio for bupivicaine is 2.0, for lignocaine it is 7.1, for ropivicaine it is 2.2. Hence, of the commonly used perioperative local anaesthetic agents, bupivicaine and ropivicaine are potentially significantly more toxic than lignocaine. Thus the appearance of seizures in the patient in question is less of a concern in that she received lignocaine, not bupivicaine. It is believed that the mechanism behind the greater cardiovascular toxicity of bupivicaine is that it much more slowly dissociates from cardiac conduction tissue than lignocaine. This prolongs the refractory period, and reduces conductivity through regular pathways. This significantly increases the risk for malignant ventricular arrhythmias.

Toxicity

Note that by “toxicity” I mean neurologic depression as a direct extension of the pharmacologic effects of the drug. Certain additional factors are likely to increase the risk of neurologic toxicity, these include respiratory (increased PaCO2) and metabolic acidosis, leading to reduced protein binding, or the administration of benzodiazepines or barbiturates.

Toxicity depends on the amount of free drug in plasma; this relates to three factors:

1. Dose given.

2. Rate of injection (the effective dose given).

3. Site of injection (the greater the blood supply to the area injected the greater the systemic absorption). Sites of absorption from greatest to least:

interpleural > intercostal > pudendal > caudal > epidural > brachial plexus > infiltration

(in this scenario the patient received drug principally by infiltration),

TREATMENT

Treatment for CNS toxicity of local anaesthetics is essentially supportive (figure 3). Ensure that the airway is patent and that the patient is breathing spontaneously. Apply supplemental oxygen. Lay the patient flat. Ensure that the patient has iv access and that intravenous fluid is running. Check the patient’s pulse and blood pressure. If the patient is unconscious, a jaw thrust may be required to prevent airway obstruction. Do not place any devices between the patient’s teeth if they are seizing. If necessary place a nasopharyngeal airway.

If the seizure does not rapidly self-resolve, then intravenous midazolam (0.05 to 0.1mg/kg), lorazepam (0.1mg/kg) or diazepam (5 – 10mg) may be administered to control seizure activity. If this fails, phenobarbitone or thiopentone may be administered intravenously. An alternative approach would be to secure the airway following induction of anaesthesia with propofol and administration of a propofol infusion. Hypoxia should be treated aggressively as should acidosis: respiratory acidosis is managed by increasing alveolar ventilation. Metabolic acidosis is resolved with restoration of oxygen flow, intravenous fluids and, in extreme cases, administration of sodium bicarbonate. The treatment for LA induced arrhythmia is Bretylium 7mg/kg. Phenytoin should not be used for seizures, because it is also a sodium channel blocker.

Intravenous intralipid® (20%) appears to be effective at minimizing adverse cardiovascular outcomes. There are many case reports and animal studies that have demonstrated rapid resolution of cardiovascular symptoms associated with this lipid emulsion. Intralipid is the major component of total parenteral nutrition. It is believed that the lipid acts as a bank for local anaesthetic – the drug has more affinity for the lipid than for cardiac tissue; as the amount of buipivicaine bound up to cardiac tissue is reduced, normal contractile function results. There are no randomized controlled trials supporting its use, and it is unlikely that there ever will be (similar to dantrolene for malignant hyperthermia). Although propofol contains lipid, the concentration is insufficient to have a beneficial effect. Intralipid is inexpensive and has a long shelf life; consequently there is no reason why it cannot be stored in any location in which anaesthesia is delivered.

The Association of Anaesthetists in Great Britain and Ireland (aagbi.org) have issued guidelines for the use of intralipid in the event of LA toxicity: initial bolus of 100ml 1.5ml/kg over 1 minute) followed by 400ml (0.25 ml/kg) over 20 mins. Repeat boluses can be administered subsequently: 100ml at 5 minute intervals repeated x2 and then 400ml administered over 10 minutes.  CPR should be continued until the circulation has been re-established. If all of this fails – cardiopulmonary bypass may be instituted until the local anaesthetic has been metabolized.

 

Figure 2: Treatment of Local Anaesthesia Toxicity

Click here for the AAGBI A4 sheet.   Click here for the accompanying notes.

CONCLUSIONS

  • Local anesthetic toxicity can be seen with local anesthetic wound infiltration, epidural catheter placement, and nerve blocks.
  • Signs of low level CNS toxicity from local anesthetics include: circumoral numbness, lightheadedness, and tinnitus.
  • Increasingly higher concentrations of local anesthetic toxicity leads to visual disturbances, seizures, loss of consciousness, respiratory and cardiac arrest.
  • The greater the blood supply at the site of local anesthetic injection, the greater systemic absorption of the drug.
  • The maximum safe doses of local anesthetics are: bupivicaine 2 mg/kg (2.5mg/kg with adrenaline), lignocaine 5mg/kg (7mg/kg with adrenaline), levobupivicaine (chirocaine) 2-3mg/kg, ropivicaine (naropin) 3-4mg/kg, prilocaine 6 mg/kg.
  • There are various causes of post-op seizures, including intracranial bleeding following craniotomy, stroke, hypoglycemia, electrolyte imbalance, hypoxia, and drug or local anesthetic toxicity.
  • Treatment for CNS toxicity caused by local anesthetics is supportive, including maintaining a patent airway, monitoring vital signs, administering IV fluids, and giving antiseizure medications.
  • Intralipid is currently recommended to prevent the development of cardiovascular toxicity associated with LA toxicity. The mechanism of action is unknown.

DRUG

LIGNOCAINE

PRILOCAINE

BUPIVACAINE

LEVOBUPIVACAINE

ROPIVACAINE
Relative potency

2

2

8

8

6
Onset

5-10 min

5-10 min

10-15 min

10-15 min

10-15 mins
Duration
without adrenaline

1-2 hours

1-2 hours

3-12 hours

3-12 hours

3-12 hours
Duration
with adrenaline

2-4 hours

2-4 hours

4-12 hours

4-12 hours

4-12 hours
Max dose
without adrenaline

3 mg/kg

6 mg/kg

2 mg/kg

2.5 mg/kg

3 mg / kg
Max dose
with adrenaline

7 mg/kg

9 mg/kg

2.5 mg/kg

3 mg/kg

4 mg / kg