Pain Pump Law Blog : Medical Device and Malpractice Lawyer & Attorney for Local Anesthetic Infusion Pump & Post-Operative Infection Cases

In a recent article entitled, Local Myotoxicity from Sustained Release of Bupivacaine from Microparticles, Padera, et.al., state:

Myotoxicity is a well-recognized side effect of local anesthetic administration, perhaps particularly of extended exposure, whether from controlled-release methodologies or from catheter-related methods. Occasionally, the consequences can be clinically significant.

These authors studied a variety of controlled-release systems designed to prolong the duration of local anesthetics. The authors gave rats sciatic nerve blocks by injecting them with different bupivacaine solutions and found muscle damage in all of the animals, with greater damage from the encapsulated (higher concentrated) bupivacaine particles than from free bupivacaine (the 0.5% bupivacaine hydrochloride solution commonly used in surgeries). Local anesthetic-induced myotoxicity generally recovers rapidly, often within two weeks, however, the authors noted some controlled-release formulations cause myotoxicity at least as far out as one month after injection.

One possible explanation of this observation is that local anesthetic myotoxicity is time-dependent. Myotoxicity was found to increase with the concentration of bupivacaine, but also markedly with duration of exposure. For example, 62 +/- 12% of cells exposed to 0.025% bupivacaine survived a 2-hour exposure, whereas only 1 +/- 2% survived at 3 weeks. It is important to note that this is an extremely weak concentration of bupivacaine: twenty times weaker than 0.5%. The authors go on to say:

This finding raises the possibility that myotoxicity could be an inevitable concomitant of long-term exposure to conventional (amino-amide and amino-ester) local anesthetics, irrespective of the technology used to deliver them. Myotoxicity is a well-known occurrence in clinical or investigational use of conventional local anesthetics. Although it can have severe consequences, it has not generated much clinical concern. In fact, intramuscular local anesthetic injection is a standard treatment for trigger points in myofascial pain syndromes, and local anesthetic myotoxicity is generally reversible. The distinction that must be made, however, is that those treatments generally involve a single-shot drug injection with a brief duration, whereas microparticulate systems can result in very high local concentrations and/or weeks of local anesthetic exposures.

The findings of this article raise alarming concerns about pain pumps. The continuous repeated exposure to tissues (especially around a healing surgical wound) with local anesthetics (known to cause cell damage and even death) over a period of 48 to 120 hours seems much more likely to result in cell damage than if the same volume of the medication was injected at a single time.

The potential for irreversible cell damage—necrosis—caused by local anesthetics and infusion pumps seems site-dependent. Pain pump manufacturers have acknowledged as much. I-Flow, in its current Directions For Use for the On-Q pump states:

To avoid complications in restrictive spaces use the lowest flow rate, volume and drug concentration required to produce the desired result. In particular:

Avoid placing the catheter in the distal end of extremities (such as nose, ears, fingers, groin area, penis, toes, etc.) where fluid may build up as this may lead to ischemic injury or necrosis.

However, this warning (also contained in I-Flow’s Technical Bulletin on hand and foot surgery) is too limited in scope. While it would apply to bunionectomies, it does not apply to any other foot or ankle surgeries, including catheter placements in the top of the foot near the ankle. This is certainly a restrictive space, made even more so when it is under a compression dressing following surgery. Two pain pump cases I have involve foot surgeries with catheter placements in this location, with disastrous complications to the patients.

The more often I read about the toxicity of local anesthetics, especially bupivacaine, the more I suspect it routinely causes damage to the patient (maybe always causes damage), but that harm is often not detected because the affected cells regenerate or scarring or other damage occurs which may not manifest itself until far in the future. Even when the damage arises to visible injury, many of these injuries are not properly diagnosed as local anesthetic tissue toxicity, but rather as post-operative infections. This is what occurred in the two foot surgery cases I mentioned above.

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On November 13, 2009, the FDA announced it will require pain pump manufacturers and the manufacturers of the local anesthetics used in them to update their product labels to contain a warning about the risk of chondrolysis following continuous infusion with local anesthetics into joint spaces after orthopedic surgery. 

One paragraph of the FDA announcement particularly caught my attention:

Local anesthetics are approved as injections for the production of local or regional anesthesia or analgesia. The approved drug labels for local anesthetics do not include an indication for continuous intra-articular post-operative infusions or use of infusion devices such as elastomeric pumps. The FDA has not cleared any infusion devices with an indication for use in intra-articular infusions of local anesthetics. (emphasis mine)

This statement confirms my contention that continuous infusion via pain pumps is an off-label use of any local anesthetic.  For example, when Hospira in its label for Marcaine (Bupivacaine) makes recommendations for maximum dose volume for particular uses including local infiltration, peripheral nerve blocks, and epidurals, these same recommendations should not be considered applicable to continuous infusion because it is a categorically different use.  

The duration of anesthesia with MARCAINE is such that for most indications, a single dose is sufficient.
Maximum dosage limit must be individualized in each case after evaluating the size and physical status of the patient, as well as the usual rate of systemic absorption from a particular injection site. Most experience to date is with single doses of MARCAINE up to 225 mg with epinephrine 1:200,000 and 175 mg without epinephrine; more or less drug may be used depending on individualization
of each case.
These doses may be repeated up to once every three hours. In clinical studies to date, total daily doses have been up to 400 mg. Until further experience is gained, this dose should not be exceeded in 24 hours. (emphasis mine)

It is clear from the focus on single doses that these recommendations contemplate traditional nerve blocks and not continuous infusion.  As I understand it, most nerve blocks are performed using far less than 175 or 225 mg of Marcaine.  Moreover, the concerns regarding dosage at these volumes have been for neuro- and cardiotoxcity; in other words, systemic and not local toxicities.  Pain pumps represent a categorically different use because of the much larger volume of local anesthetics infused and the great duration of exposure the affected tissues have to the mediation —typically at least two days and as long as five days post-operatively.

Nonetheless, I-Flow's dose recommendations for its own products explicitly rely on the 400 mg total daily maximum recommendation for Marcaine as a toxic ceiling below which pain pumps allegedly may safely continuously infuse this medication.  A commonly-used 100 ml 2 ml/hr. pain pump would mean a 24-hour dose of 240 mg (24 hrs x 2 ml x 5 mg/per ml).  On what evidence are pain pump manufacturers relying that this volume of 0.5% Marcaine is safe for continuous infusion following any surgical procedure? 

Given the known toxic properties of Marcaine and other local anesthetics, in my opinion the proper standard for physicians and manufacturers should be:  what are the lowest dose, concentration, and flow rate that will produce the desired analgesic effect?  Pain pump manufacturers have a financial incentive not to frame the use of their produce in these terms, however.  Because they market their products to surgeons as a more effective alternative to oral narcotics, they are inclined to recommend the use of the most potent of the commonly-used anesthetics--Marcaine--at a high concentration--0.5%--and in large volumes.  More on these issues in my next post.  

 

 

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In a 2004 Product Insert, I-Flow Corporation stated its On-Q PainBuster was intended to provide continuous infusion of a local anesthetic directly into an intra-operative site for post-operative pain relief. By April 2009, I-Flow had modified this language to say that the product is intended to provide continuous deliver of medication (such as local anesthetics) to or around surgical wound sites and/or close proximity to nerves for pre-operative, peri-operative and post-operative regional anesthesia and/or pain management.

This seemingly minor change is significant because it is indicative of potential problems with pain pump catheters being placed directly into a surgical site. (Although images from I-Flow's most recent product materials still show the catheter being inserted directly into the wound site).

In 2003, Brower and Johnson published an article entitled Adverse Effects of Local Anesthetic Infiltration on Wound-Healing.  As background they explain:

Wound infiltration with LA (local anesthetics) can provide excellent analgesia under at least some circumstances, although optimal dose and wound installation technique are not well-defined. However, there is a substantial body of literature suggesting that LA infiltration can have deleterious effects on wound healing. These reports are spread across a wide range of literature, including surgical, anesthetic, ophthalmologic, pharmacologic, and cellular bio-chemistry and are often not appreciate in total. The risks reported therein should be considered in clinical decisions to use wound infiltration and in future studies to assess its benefits.

In reviewing the available studies on the effects of local anesthetics on wound healing, the authors report a number of noteworthy conclusions:

Overall wound healing may also be affected by any effect of LA on a cell type adjacent to the wound. In particular, myotoxicity from local infiltration of LA, particularly bupivacaine, could weaken the wound site even if fibroblasts and other cells directly involved in wound healing were not affected.
Taken together with the body of published studies discussed here strongly suggests that LAs can inhibit the first two stages of wound healing, the inflammatory and granulation/proliferation stages. Inhibition of healing appears to be a general property of all commercially available LAs.

Pain pump manufacturers want surgeons to be able to place catheters directly into the wound site because it is easier to visualize than placement for a nerve block, which might require an anesthesiologist. These devices are marketed to surgeons, in no small part, as means for them to perform (and bill for) an additional procedure on their own. The wound healing problems raised by Brower and Johnson seem quite consistent with the sorts of adverse events involving pain pumps (beyond chondrolysis) that have been reported to the FDA.

Perhaps if the local anesthetic is not directly bathing the surgical wound, but an area proximate to it, the patient can still receive pain relief at this site without negatively affecting wound healing. I am aware of cases, however, in which the catheter was placed some distance to the surgical site and severe wound healing complications developed anyway. It is possible these instances had more to do with the location of the surgeries--the dorsum (top) of the foot--than whether the catheter was placed in or out of the incision.

More positive perspectives on local anesthetic infusion directly into a surgical wound site include portions of a book chapter by Rawal (2006) (PDF) and an editorial by Kehet and Liu (2007) (PDF).

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The controversy and litigation over local anesthetic infusion pumps—pain pumps—has to date largely been focused on shoulder surgeries and chondrolysis. There is a perception that these devices were intended by their manufacturers for use primarily in the shoulder. I have seen some complaints and discovery documents from plaintiffs lawyers even refer to these devices as “shoulder pain pumps.”

In fact, these devices have been and continue to be routinely used in surgeries throughout the body. What hasn’t received sufficient attention is the fact that numerous adverse events involving types of surgery other than to the shoulder have been reported for many years, including prior to the problem of chondrolysis in the shoulder being identified with these devices.

In 2004, two FDA researchers published a journal article, Local Anesthetic Infusion Pump Systems Adverse Events Reported to the Food and Drug Administration. They summarized 40 injuries reported to the FDA that followed the use of pain pumps at a variety of surgical sites including orthopedic, gastrointestinal, and podiatric. The complications encountered with the pain pumps included tissue necrosis, surgical wound infection, and cellulitis. 45% of the surgeries were orthopedic, typically total knee replacements. 20% were for podiatric surgeries, including bunionectomies, plantar fasciotiomies, and others.

All of the reports that specified the local anesthetic involved Bupivacaine (most common trade name—Marcaine) with or without adrenaline. The consequences of these adverse events were typically severe and required intervention and additional medical and surgical treatment. The authors’ review of the literature found little had been written to support a causal link between pain pumps and the complications that had been reported to the FDA. Therefore, the authors’ conclusion was tentative and stated the reports may represent sentinel events, i.e., an early warning that is representative of a widespread problem, or alternatively, these may be isolated incidents.

The FDA Medical Device adverse event database shows that at least 60 additional adverse events involving tissue necrosis and other wound-healing complications and pain pumps manufactured by I-Flow Corporation (the largest manufacturer of pain pumps) alone have been reported to the FDA since December 2003, the end-point of the article’s scope. It seems likely these events are not isolated and indicate a serious problem with these devices, beyond their likely relationship to chondrolysis in shoulder surgeries. There is a substantial body of evidence that Bupivacaine, even without epinephrine, causes severe damage to a variety of human tissue including muscle, subcutaneous skin, as well as cartilage.

Prior to the advent of pain pumps, local anesthetics were typically used in relatively small amounts to provide nerve blocks or in the margins of surgical wounds to provide pain relief. Even if harm to tissues occurred it likely went unnoticed because cells damaged by local anesthetics typically regenerate and surgical pain and dressings may have masked such harm. Pain pumps infuse much larger volumes of these drugs, which appears to be especially problematic in certain areas of the body such as joint spaces--shoulder and knee--and the foot.

I believe pain pump manufacturers have improperly relied on the dose and concentration recommendations made by the makers of Bupivacaine for past uses, without adequate research to support its safe use when continuously infused in larger volumes. Even when pain pump manufacturers have been confronted with evidence of adverse events involving their products, they have failed to adequately warn surgeons and the public of these risks. It is likely that hundreds of patients, if not more, have suffered injuries, many life-altering, as a result.

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