Date Published: September 29, 2012
Publisher: Hindawi Publishing Corporation
Author(s): Sarah Ciechanowicz, Vinod Patil.
The accidental overdose of local anesthetics may prove fatal. The commonly used amide local anesthetics have varying adverse effects on the myocardium, and beyond a certain dose all are capable of causing death. Local anesthetics are the most frequently used drugs amongst anesthetists and although uncommon, local anaesthetic systemic toxicity accounts for a high proportion of mortality, with local anaesthetic-induced cardiac arrest particularly resistant to standard resuscitation methods. Over the last decade, there has been convincing evidence of intravenous lipid emulsions as a rescue in local anesthetic-cardiotoxicity, and anesthetic organisations, over the globe have developed guidelines on the use of this drug. Despite this, awareness amongst practitioners appears to be lacking. All who use local anesthetics in their practice should have an appreciation of patients at high risk of toxicity, early symptoms and signs of toxicity, preventative measures when using local anesthetics, and the initial management of systemic toxicity with intravenous lipid emulsion. In this paper we intend to discuss the pharmacology and pathophysiology of local anesthetics and toxicity, and the rationale for lipid emulsion therapy.
Local anesthetics (LAs) can be defined as drugs that reversibly block transmission of a nerve impulse, without affecting consciousness. Medical use of local anesthetic agents began some years after the isolation of cocaine from Peruvian coca in the 1860s. Chance discovery in 1884 by Freud while using cocaine to wean a morphine addict lead Koller to use cocaine successfully in ophthalmic surgery as a topical anesthetic. Halsted and Hall took more invasive steps by directly injecting cocaine into oral cavity nerves in order to produce anesthesia for removal of a wisdom tooth .
The physicochemical properties of LAs determine their properties as anesthetic agents. They have three structural groups, an aromatic ring, connecting group (ester or amide), and an ionizable amino group. This lipid-soluble hydrophobic aromatic group and a charged, hydrophilic amide group enables them to exert their effects by two mechanisms: in their uncharged (unionized) state they lipid soluble and able to traverse the lipid bilayer of the neuronal cell membrane, to then gain a hydrogen ion and become ionized making them able to bind intracellularly to voltage-gated sodium channels, rendering the channel reversibly inactive, and so unable to allow for sodium entry to generate and propagate the action potential  (see Figure 1). Binding can also occur to the closed sodium channel to retain its inactive state. Secondly, LAs have direct effects on the lipid bilayer, disrupting impulses by incorporating into the cell membrane, causing expansion [10, 11]. The sensitivity of nerve fibers depends upon their axonal diameter and degree of myelination with small, myelinated fibers more susceptible. Generally the small pain and temperature fibers (C unmyelinated, A-δ myelinated) are blocked first with the larger touch and pressure (A-Υ, A-β) fibres next, and large muscle tone and postural A-α fibres last. It is thought that the prolonged action potential of smaller fibres provides more time for LA entry, and more frequently stimulated nerves show increased susceptibility from a high degree of open channels. The story does not end there, however, in addition to blocking sodium channels, newer amino amide ropivacaine has been found to bind to human cardiac potassium channels (hKv 1.5) to block repolarization of the membrane . A number of anesthetics, including bupivacaine and ropivacaine, have also been shown to block L-type Ca2+ channels in rat cerebrocortical membranes. From a systemic viewpoint, LAs may improve pain by inhibiting local inflammatory response to injury by decreasing inflammatory cytokine release from neutrophils.
Potency is decided by the lipid solubility of the agent and can be expressed as a lipid : water partition coefficient (LWPC), the ratio of the amount of agent in each phase. High coefficients increase lipophilic properties and allows for ease of passage into the cell membrane thus facilitating potency. Onset of action is determined by the ionization constant or pKa value, which determines the proportion of ionized to unionized form of the agent at a given pH. Agents with a pKa value closer to the physiological pH permit more LA in the unionized, lipid soluble form to enter the cell. So factors that alter tissue pH also affect the proportion of LA in the unionized form and hence can slow onset of action in an acidic, infected wound. Table 1 demonstrates these properties in some common anesthetic agents.
The primary aim of local anesthetic administration is to saturate the targeted nerves while causing minimal systemic absorption. Infiltration of skin, subcutaneous tissues, intrathecal, and epidural spaces will result in varying absorption into the systemic circulation depending on the surface area for absorption and vascularity of the area. Intercostal muscles and epidural administration being particularly susceptible, and in dentistry the gingiva of the maxillary alveolar ridge is prone to inducing rapid systemic absorption. Lignocaine has a vasodilatatory effect and so is often mixed with adrenaline or phenylephrine to reduce vascular absorption and hence prolong action and reduce the risk of systemic toxicity. Conversely, cocaine is a potent vasoconstrictor.
20% lipid infusion is the first safe intravenous lipid emulsion (ILE) used in medicine and has been around since 1962 for its use in parenteral nutrition. The commercial preparation Intralipid 20% is manufactured by Fresenius Kabi, 1 liter consists of 200 g purified soybean oil, 12 g purified egg phospholipids, and 22 g anhydrous glycerol, and it is a source of omega-3 and -6 essential fatty acids with total energy content 8.4 MJ (2,000 kCal). ILEs use in LAST came about from an unexpected finding by Weinberg in 1998. Following a case report of a carnitine-deficient patient showing increased susceptibility to bupivacaine cardiotoxicity, he postulated the impaired fatty acid oxidation was the etiology and in seminal work, preloaded rats with ILE prior to bupivacaine in hope to establish this. The result was quite the opposite, with an increase in the mean lethal dose (LD50) by 50% . He later went further to demonstrate the efficacy of ILE by rescuing dogs from bupivacaine-induced cardiac arrest . ILE therapy for treatment of LAST is now well established, following a crop of over 19 peer-reviewed case reports appearing since Rosenblatt’s successful application of ILE to clinical practice in 2006 , and supports the use of ILE for bupivacaine, levobupivacaine, and ropivacaine cardiotoxicity [56–61]. This year we also saw a successful case report from seemingly intractable lignocaine-induced cardiac arrest .
Prevention is better than cure, and although no single preventative measure can eliminate the risk of developing LAST, they do provide improved safety. Regarding site of injection, care must be taken to avoid intravascular injection and awareness of tissues prone to rapid uptake, such as the head and neck, is useful. Since the introduction of the measures to prevent inadvertent intravascular injection that began with the epinephrine test dose for labor epidurals by Moore and Batra in 1981 , the incidence of LAST has fallen 10–100 fold . The following methods, although singularly unproven, likely promote safety.
Vigilance is required when performing procedures that have a potential for systemic toxicity. There are numerous examples of local anesthetic systemic complications in the literature, many in the hands of nonanesthesiologists. We see that strategies to reduce the risk of LAST can never eliminate its risk. Although uncommon, the consequences can be fatal. Advances in ILE therapy and understanding is providing a life-saving rescue in the most dreaded situations faced by practitioners, and further progress will likely improve on our safe use of LAs in the future. Rapid identification of toxicity and a good recall of the ILE therapy regimen can save lives, but we need to expand awareness to practitioners in remote locations such as outpatients, offices, and especially those who work without an anesthesiologist. We encourage these facilities to put together a “rescue kit” in a specified location with the current guidelines readily available. LAs are used more frequently by surgeons and dentists than anesthesiologists, and on that note we feel that the respective colleges should also develop guidelines for management of LAST incorporating lipid emulsion therapy.