Bupivacaine is the preferred local anesthetic to achieve long-lasting peripheral nerve blockade

PRO

JC Gerancher, MD

Which local anesthetic should we choose to achieve long-lasting peripheral nerve blockade? Such a straightforward question deserves a direct answer. My direct answer is "bupivacaine." However, I believe practices vary because the question is not as straightforward as it seems for the following two reasons: 1. It is difficult to characterize the clinical duration of any given local anesthetic because so many clinical factors besides the local anesthetic we choose influence the duration of blockade we achieve. Long-lasting peripheral nerve block solutions at many institutions have evolved into a routine `cocktail' containing one or more adjuncts to the long-lasting local anesthetic— each individually demonstrated to prolong the duration of one local anesthetic or another, in one clinical situation or another (table two).<sup>1,2,3,4</sup>. Furthermore, local anesthetics are currently administered in doses and concentrations that vary by as much as 2-fold among practitioners<sup>5,6</sup>. Practitioners not only utilize many different solutions but also inject these solutions using various technical approaches at many different anatomic sites. Surgeries and surgeons differ just as greatly, and these surgical factors bring their own differing requirements for analgesia. Patients too are individuals: analgesic duration has been found to vary greatly among patients even when the above factors are controlled (table one and two). Compounding these issues, many blocks provide analgesia into the wee-hours of the morning when duration is inconvenient or impossible<sup>7,8</sup> to monitor accurately. Then, when we are able and willing to carefully monitor duration, is the duration of surgical anesthesia, residual sensory blockade, or first request for additional analgesics that which we most often report as "duration?" Deciding `which local anesthetic' first requires a careful look at the literature. The available controlled, randomized studies that have compared the most clinically meaningful outcome— time until first request for additional analgesia after peripheral nerve block— are listed in table one.

2. Issues other than achieving a long analgesic duration enter into our decision-making process when we reach for a vial of local anesthetic. Factors such as motor/sensory differential blockade, clinical latency, and success rate are important as well. Added to these, the issues of acquisition cost and patient safety guide our choices. The controlled randomized studies here too are helpful when it comes to assessing the clinical utility of local anesthetics. Furthermore, I believe the literature is equally useful in making a rational choice based on the additional factors of patient safety balanced with cost (table three).

Because of many of the clinical issues noted above, relatively few studies have successfully compared the time until first request for additional analgesia after long-lasting peripheral nerve block. Those comparing this outcome have compared bupivacaine and ropivacaine and are listed in table one. In most of these studies, 50% more ropivacaine was compared to less bupivacaine. (Equal volumes of 0.75% ropivacaine and 0.5% bupivacaine were compared). Despite epinephrine being a common and recommended⁹ adjunct, most studies looked at peripheral nerve block with local anesthetic alone. In these studies, variability of analgesic duration among individual patients was usually large. Bupivacaine always provided for a longer duration of analgesia^6,1

^0-15. When studies were able to demonstrate a statistically significant difference in analgesic duration^10,11, it was always bupivacaine that produced an extended enough blockade to overcome the variability of block duration in individual patients. Importantly, this longer duration of analgesia occurred often despite the use of less bupivacaine and no epinephrine.

Bupivacaine and levobupivacaine peripheral nerve blocks have been compared only once and these authors reported the duration of residual sensory block (not first request for analgesia)¹⁶. In this single study the duration of residual sensory supraclavicular block was 17 hours for levobupivacaine and 16 hours for bupivacaine (n.s.).

Table One: Time until first request for additional analgesia: bupivacaine versus ropivacaine peripheral nerve blockade.
Author	Block	Equal dosing?	Epi?	Bupivacaine (hours)	Ropivacaine (hours)	Significance
Greengrass10	Lumbar/Sciatic	Y	Y	17+/-3	13+/-2	P<0.001
Fanelli11	Femoral/Sciatic	N	N	14.6+/-5.2	11.1+/-3.7	P<0.05
Klien12	Interscalene	Y	Y	13+/8	12+/-4	n.s.
Raeder13	Axillary	N	N	13+/-1.3	12+/-1.2	n.s.
Vaghadia14	Supraclavicular	N	N	12	11	n.s.
Bertini15	Axillary	Y	N	11.1+/-3.5	10.9+/-3.7	n.s.
Fanelli6	Interscalene	N	N	10.9+/-3.9	10.7+/-2.0	n.s.

Although prolongation of short-acting local anesthetics by clonidine, verapamil, and opioid adjuncts has sometimes been dramatic,^1-3,17 analgesic duration does not exceed that reported for bupivacaine by other authors (table1 versus table 2). Although tetracaine is sometimes advocated as an adjunct to short-acting local anesthetics, the limited information available regarding peripheral nerve block with tetracaine¹⁸ suggests it does not last any longer than bupivacaine. The duration of analgesia attainable using adjuncts in combination with one of the long-lasting anesthetics deserves more study⁴. It is conceivable that some combination of epinephrine, clonidine, verapamil, opioid, or all of the above may be found to prolong the duration of bupivacaine analgesia even further.

Table Two: Time until first request for additional analgesia: adjuncts
Author	Block	Solution	Duration
Singelyn 1	Axillary	1% mepivacaine +1:400,000 epi + 0.5mcg/kg clonidine	8+/-4
Moore 18	Femoral/Sciatic	0.25% tetracaine	10+/-2
Nishikawa 2	Axillary	1.5% lidocaine +1:200,000 epi + 100 mcg fentanyl	5+/-1
Reuben 3	Axillary	1.5% lidocaine + 2.5 mg verapamil + 5mg morphine	12+/-4
Casati 4	Femoral/Sciatic	0.75% ropivacaine + 1 mcg/kg clonidine	17+/2

Sensory/motor differential blockade is an aspect of clinical utility that could potentially be desirable in most clinical situations. Unfortunately, studies have not demonstrated analgesia without significant motor block following peripheral nerve blockade with bupivacaine, levo-bupivacaine, orropivacaine^{1 -16, 18}. Latency until surgical anesthesia is another important clinical issue. Studies generally document that the long-lasting agents take a long time (15-30 minutes) to produce surgical anesthesia. All studies comparing equal amounts of long lasting local anesthetic^{5,7,8,10,12,16,18} except for one¹⁵ found no difference in their latencies. A single study¹⁵ found a shorter latency with ropivacaine (16+/-4minutes) as compared to bupivacaine (22+/-8 minutes). (These authors also achieved a 100% success rate with both drugs using a multiple nerve stimulation axillary block technique in which all four nerves were located within five minutes or patients were excluded from the study. Epinephrine was not used in their solutions of 0.75% ropivacaine, 0.5% ropivacaine, and 0.5% bupivacaine.) Both these latencies (16 versus 22 minutes) are long and probably clinically comparable. Shorter latency has been achieved with the shorter-lasting anesthetics—lidocaine and mepivacaine^11,17,18. Regardless of long-lasting local anesthetic dose compared, no study has

shown differences in block success as measured by need for additional peripheral nerve blockade or general anesthesia^{5-8,10-16,18,19}. In terms of clinical utility then, the current literature suggests that lidocaine or mepivacaine may be better choices when latency is a pressing issue but that bupivacaine, levobupivacaine, and ropivacaine (at equal doses) are comparable performers in terms of motor block and success when a long-lasting block is desirable.

The acquisition cost of levobupivacaine (Chirocaine) and ropivacaine (Naropin) are two to four times greater than that of generic bupivacaine. This relative cost difference is arguably minor in the scheme of anesthesia and surgical care for an individual patient. (The added cost of one vial of levobupivacaine or ropivacaine is less than the cost of an endotracheal tube and circuit or a vial of one of the newest muscle relaxants.) However, the individual patient measures a benefit when we choose the less expensive long-lasting local anesthetic because bupivacaine provides for a longer duration of analgesia. The hospital administrator measures a benefit because she is able to multiplying bupivacaine's lower cost by the cartons and cartons of local anesthetic the anesthesiologists at her hospital are administering over the course of a year

as part of their growing interest in peripheral nerve blockade. The anesthesiologist and surgeon break even: bupivacaine provides for equal motor block, equal success rates, and a latency that is clinically comparable to that of ropivacaine and levobupivacaine. Comparatively then, bupivacaine gives the individual patient longer-lasting analgesia, while providing more `bang for the buck.'

Safety is an extremely important issue because peripheral nerve blockade routinely involves the injection of local anesthetic in large enough amounts to cause systemic (CNS and cardiac) toxicity if injected entirely intravascularly. Obviously, an inexpensive drug that works well but is unsafe is only still an unsafe drug. Two recent studies highlight the safety of local anesthetics in a way clinically relevant to how they are used for peripheral nerve block. In one of these studies open-chest dogs were given infusions of bupivacaine, levobupivacaine, ropivacaine, and lidocaine to the point of cardiovascular compromise²⁰ and in the other study to the point of cardiovascular collapse²¹. The study design allowed for comparison of plasma concentrations and effects of these local anesthetics at clinically equivalent endpoints for each drug. At the same time, these studies approximate the clinical situation of accidental intravascular injection of a huge dose of local anesthetic during peripheral nerve block. The data from these studies (table three) suggest that lidocaine is the safest of the four local anesthetics: higher plasma levels were achieved prior to cardiovascular collapse and all animals could be resuscitated. There was no statistically significant difference in mortality among bupivacaine, levobupivacaine, and ropivacaine animals. However, the animals that received ropivacaine had significantly higher plasma concentrations at the point of collapse, compromise, and once resuscitated. These differences in plasma concentrations lead the authors to conclude that ropivacaine (versus bupivacaine) may provide "a greater margin of safety when larger volumes and high concentrations are used to establish upper and lower extremity nerve blocks for surgical anesthesia."²¹ Other animal²² and human²³ studies demonstrate that levobupivacaine too produces less cardiac depression when compared to bupivacaine.

In the rare clinical event of an intravascular injection of local anesthetic in an amount large enough to cause cardiac collapse, ropivacaine and levobupivacaine probably have a safety advantage over bupivacaine. In this specific, disastrous clinical situation, short-acting lidocaine probably provides a margin of safety that is even greater. No comparative studies exist to suggest that intravascular injections in patients are less likely to occur with ropivacaine or levobupivacaine, that intravascular injections can be reconized earlier or more easily, or that resultant CNS morbidity is any less. Therefore, in my opinion, the potential safety margin provided by ropivacaine or levobupivacaine in the setting of massive intravenous overdose cannot necessarily be generalized to say that the newer long-lasting local anesthetics are `safer'. The techniques already developed<sup>9</sup> to make bupivacaine a `safe' local anesthetic—skilled needle placement, aspiration, incremental dosing, appropriate dosing, and the use of epinephrine as an intravenous test dose—remain of paramount importance to patient safety regardless of long-lasting local anesthetic choice.

 

Table three: Resuscitation from cardiovascular collapse in dogs: bupivacaine, levobupivacaine, ropivacaine, and lidocaine
	Bupi	Levo	Ropi	Lido	Significance
Plasma concentration at the point of 25% decrease in C.O. (ug/ml) 20	3.6	3.3	5.0	15.8	ido>bupi,levo,ropi
Plasma concentration at the point of cardiovascular collapse (ug/ml) 20	5.7	9.4	19.8	81.8	Lido>bupi,levo,ropi Ropi>bup
Plasma concentration immediately following resuscitation (ug/ml) 20	0.51	1.14	3.9	17.4	Lido>bupi,levo,ropi Ropi>bup
% of animals successfully resuscitated within 20 minutes 21	40%	40%	80%	86%
% of animals requiring prolonged (> 20 minutes) but successful resuscitation 21	10%	30%	10%	14%
% mortality ( animals failing prolonged resuscitation) 21	50%	30%	10%	0%	Lido<bupi,levo, ropi

In summary, bupivacaine has the longest documented duration of any local anesthetic when used for peripheral nerve block. This advantage combined with low cost make bupivacaine the preferred local anesthetic to achieve long-lasting peripheral nerve blockade. Using adjuncts to further prolong bupivacaine peripheral nerve blockade (and perhaps even improve patient safety²⁴) deserves continued study. The comparative analgesic duration of bupivacaine versus levobupivacaine peripheral nerve blockade with and without additives deserves further study as well. With equal dosing, bupivacaine has motor block, latency, and block success clinically equal to that of levobupivacaine and ropivacaine. Ropivacaine and levobupivacaine probably provide a greater margin of safety in the specific situation of a huge intravascular injection and cardiovascular compromise. Bupivacaine, levobupivacaine, and ropivacaine are all safe local anesthetics for peripheral nerve blockade.

JC Gerancher, MD
Assistant Professor
Wake Forest University

Bowman Gray Campus
Winston-Salem, NC

References

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