Helpful Reviews of Local Anesthetics

With pain pumps, there is a tendency among lawyers and lay persons to focus on the device and not on the drugs within the device.  The properties of local anesthetics, in conjunction with the mechanism of continuous infusion, are a key aspect of the risk of injuries involved with pain pumps.  Therefore, I think it is important to have some basic familiarity with the various local anesthetic agents. 

The following are links to helpful articles (all accessible for free online) and websites.  Most of these are heavy on pharmacology, but I would encourage you not to be scared off by this; I believe you can still gain some important insights:

1) www.nysora.com/regional_anesthesia/equipment/3116-local_anesthetics.html?print.  The New York School of Regional Anesthesia's site has several thorough, informative articles which help to put pain pumps into the larger context of local and regional anesthesia.

2) This book chapter from Emergency Medicine: A Comprehensive Study Guide, 6th Edition (2004) is a very good overview of local anesthetics and their common uses.

3) This 2007 presentation, by Christine Szadkowski is effective in conveying technical information graphically.  Especially helpful on dosage issues, on which European researchers seem to be far ahead of most of their European counterparts.

4)  2005 Article from a British journal.  Scholarly, but still fairly accessible.

 

Design Defect vs. Failure to Warn

In its most recent (April 2009) Directions For Use, I-Flow includes the following language in the Warnings: “To avoid complications in restrictive spaces, use the lowest flow rate, volume and direct concentration to produce the desired result.” Whose responsibility is it to make these determinations? I-Flow and other pain pump manufacturers clearly believe it is solely the physician’s responsibility. After all, it’s the doctor who decides to use the device, which model device to use, what drug to fill it with, and where to place the catheter. However, I strongly believe pain pump manufacturers cannot and should not be able to shift all of the responsibility for these decisions onto physicians.

These manufacturers have a duty to design a product reasonably safe for its intended uses, including surgeries in confined spaces such as the foot, ankle, wrist, hand, and knee. However, when they decided at what volumes to design the balloon or syringe of their pumps and at what flow rate the pumps would infuse local anesthetics, they did not start out by asking what is the lowest flow rate, volume and drug concentration needed to produce pain relief. The standard model pump made by most manufacturers has a 100ml volume and a 2ml/hr flow rate. Is this the lowest volume and flow rate necessary to produce the desired result? I don’t believe pain pump manufacturers know the answer. More disturbingly, I don’t think they believe they need to know. Further, because their competition in the post-operative pain relief market is narcotics, they have an incentive to err on the side of higher volumes and flow rates. Finally, I don’t think most of the surgeons who use pain pumps know the answer to this question either.

It appears that at the outset manufacturers believed that as long as their products delivered local anesthetics below the drug manufacturer’s maximum recommended doses (eg. 400mg for Marcaine), at which the drug may be toxic, there would be little risk of adverse effects. Staying with Marcaine as an example, at 5mg/ml, a pump with a 2ml/hr flow rate x 24 hours would infuse 240mg in the first day of use. (This is assuming a true 2ml/hr flow rate, which is not accurate for most pumps, as I have written about previously HERE).  However, the 400 mg maximum daily dose for Marcaine is to guard against the risk of systemic toxicity, such as cardiovascular and neurological, and not local toxicity. There is ample research on the toxic effects of local anesthetics, especially Marcaine, to tissues, as I have written about here and here.   Moreover, continuous infusion is not a listed use of local anesthetics by their manufacturers. The approved uses include infiltration/injections, nerve blocks and epidurals. These uses typically involve a single injection, in lower overall volumes, and where large volumes are used, they are directed away from the surgical site.

Until recently, I had been trying to fit the facts of the pain pump cases I am handling into a failure to warn theory. This argument is essentially that the manufacturer was on notice of numerous adverse events similar in nature to those experienced by my clients and was too slow to issue warnings of such risks to its surgeon customers and, when they did issue warnings, the warnings were substantively inadequate and inadequately communicated. While I continue to believe this is a legitimate argument, it is vulnerable to the defense that even had the manufacturer issued a more strongly-worded warning at an earlier time, it may well have made no difference to the patient’s outcome if there is evidence that the surgeon would not have read the warning to begin with.

I have come to believe there is a much stronger design defect claim to be made in these cases. The device manufacturers adamantly contend that all of the crucial decisions regarding the use of their products are in the hands of the surgeon and that you wouldn’t want to obligate the device manufacturer to impose its own decisions as this would limit the ability of the surgeon, who best knows the patient’s needs, to make these decisions. On these grounds, pain pump manufacturers liken their product to a syringe in which the physician makes all the decisions relating to the medication dispensed to the patient. I have sought to respond to this argument in a previous post. ( My response is essentially that the device manufacturer has already made the most important decisions regarding the device—volume and flow rate—before it ever reaches the hands of the doctor. Therefore, no manufacturer is implicitly making recommendations regarding volume and flow rate and that these are reasonably safe. So, this gets us back to the question of whether a 100ml volume pump with a 2ml/hr flow rate is reasonably necessary to provide pain relief to most surgical patients. If the answer to this question is no and there is significant evidence that such a volume and flow rate create a risk of harm to patients, especially in particular procedures, then I believe there is a strong argument that the devices have been defectively designed.

I believe I-Flow acknowledged this problem when, in October 2004, it introduced a new model pump—with 100ml volume and a 1ml/hr –specifically designed for small incisions, including foot, ankle, and hand procedures, hernia repair, laparoscopic procedures, and pediatric surgery. This model device clearly was designed to reduce the risk of local anesthetic building up in a confined space and causing harm to tissues. Inexplicably, however, it appears that I-Flow failed to market this model pump towards its intended audience. Thus, I have argued in the foot surgery cases I have had:  Was there an alternative design that could have likely prevented my client’s injuries? Yes. Did it exist? Yes. Who designed it? The defendant. 

In my cases, I don’t believe the surgeon was even aware such a model pump existed and he always used a pump with a 2ml/hr flow rate. I-Flow’s response has been, well, that’s the surgeon’s choice and he knows exactly how much medication he wishes to use and how quickly it should be delivered, and where it should be delivered to. This sort of an argument from the device manufacturer would have more weight if the devices were primarily being sold for use by anesthesiologists. However, the customers for these devices are surgeons, who are not experts in the use of higher volumes of local anesthetics. Surgeons are trained to use small amounts to inject around wound sites pre-op or post-op. Nerve blocks or epidurals, which use higher volumes of local anesthetics, can only be performed by anesthesiologists. Continuous infusion is an off-label use and it is a use that is being marketed to non-experts with these drugs—surgeons.

This gets to why, in my opinion, the learned intermediary defense in these cases is so problematic. In my cases, when I asked the podiatrist about his experience with local anesthetics, he replied that he was “Probably expert on them. The people I think that would know more about them than me is a chemist that developed them.” A pain pump manufacturer would likely think this would be helpful to them in making a non-party defense. However, such a statement cuts the other way too: this is the guy you are saying is a learned intermediary? Who used two 100ml 2ml/hr pumps filled with 0.5% Marcaine in my client’s foot? Who admitted he was unaware of the 400mg maximum daily dose for Marcaine? I suspect there are dozens, if not hundreds of surgeons like this foot surgeon who believe they are experts with local anesthetics because they have used them scores of times in high volumes in pain pumps.
 

Further Thoughts on the Significance of Unreliable Flow Rates in Pain Pumps

In a previous post, I discussed the fact that disposable pain pumps have quite inaccurate flow rates.  Also bearing on this issue is a 2008 article by Remerand, et al, concerning an examination of the reliability of a total of 430 Baxter Infusor LV5 and  Braun Easypump devices.  This study found:

--After connection to the catheter, over 20% of the pumps did not deflate correctly, with either a delay in deflation or no deflation at all.

--Flow rates differed from the manufacturers' +/- 15% accuracy in 47% of the Easypump and 34% of the Infusor devices.

A 2002 article by Ilfeld, et al, also found delivery rates of pain pumps to be widely variable in practice from manufacturers' stated rates.   This study found both ambient and skin temperature can have significant effects upon flow rates. 

These articles are by anesthesiologists examining the use of these devices to provide continuous regional postoperative analgesia; in other words, continuous nerve blocks.  Many if not most disposable pain pumps are marketed to surgeons to be employed directly in or around a surgical site.  Anesthesiologists might be expected to be more aware of the inaccuracy of the flow rates in these devices and be able to adjust the volume and duration of the anesthetic accordingly.  On the other hand, I would not think most surgeons are likely to be aware of these issues and consider them in their deployment of pain pumps. 

What are the implications? If a pump underinfuses, perhaps the harm is no more than less than adequate pain relief.  However, if a pump overinfuses, it seems to me that the potential negative effects depend greatly on the catheter placement.  More confined spaces such as the foot, ankle,  knee, hand and wrist seem especially prone to build-ups of local anesthetics from pain pumps, causing blistering and tissue necrosis.  A more rapid infusion of local anesthetic into such an area than a surgeon expects (from the device labeling) would certainly seem to raise the risk of an adverse event.  Certainly, overinfusion in or around a joint space would likely increase the risk of cartilage destruction. 

I suspect that most of the time the harm to the patient remains undetected or unattributed to the pain pump.  Harm to muscles and deeper tissues caused by excessive amounts of local anesthetics might not become apparent for a long period, if ever.  Many wound healing complications are attributed to infection as opposed to local anesthetic toxicity.  Pain in and around a surgical site may well to attributed to the trauma of the incision as opposed to damage to deeper tissues caused by local anesthetics.   Moreover, as shown by the fact that few if any knew until recently  that local anesthetics could destroy cartilage cells, I believe it's likely that there is regular harm to other types of cells that remains unknown.  

 

 


 

 

 

 

Maximum Recommended Doses of Local Anesthetics: the Significance for Pain Pumps

Many pain pump manufacturers include provisions in their product materials such as this from I-Flow's current Directions for Use for the On-Q Pump:

Medications or fluids must be administered per instructions provided by the drug manufacturer. Physician is responsible for prescribing drug based on each patient’s clinical status (such as age, body weight, disease state of patient, concomitant medications, etc.).

Nonetheless, the companies unavoidably make recommendations regarding the local anesthetics to be used in their products. Because these devices are intended to be used solely with local anesthetics and they are manufactured with preset volumes and flow rates, pump manufacturers assume a responsibility to ensure that these volumes and flow rates are reasonably safe for the procedures for which they are sold.   I previously made this point in my post titled Why a Pain Pump is not a Syringe.

Pain pump manufacturers rely on the dose recommendations of local anesthetic manufacturers in determining what they believe to be safe volumes and rates of infusion.    However, as I've also argued previously, continuous infusion of local anesthetics is not an indicated use of local anesthetics and the maximum recommended dose information is based on concerns of systemic toxicity not on the risk of direct harm to tissues or cartilage.  For many types of surgical procedures, I suspect the companies failed to conduct any testing focused on the safety in patients of various volumes, flow rates, and concentrations of local anesthetics.

With this post, I want to return to the issue of maximum recommended doses of local anesthetics, because I think it is one of the key points to focus on in legal claims involving pain pumps.   Not only are these maximum recommended doses suspect for reliance in pump pumps because these devices are an off-label use, the dose levels may not be supported by good science to begin with. 

The following is from the abstract of "Maximum Recommended Doses of Local Anesthetics:  A Multifactorial Concept," a 2004 article by Rosenberg, et. al. 

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Off Topic--A Coloring Book for Executives

I am venturing off topic to share a document I find quite funny, A Coloring Book for Executives.   I ran across it in an antique store.  Published in 1961, it's sort of Mad Men meets Mad Magazine.  I hope there are others out there to whom it may appeal. 

510Ks, Substantial Equivalence and Pain Pumps: Part Three, the Inverted Pyramid

I want to expand upon what I wrote about in prior posts here and here on the FDA 510K approval process and "substantial equivalence."   I've been trying to better understand how the pain pump market originated and expanded.  Below is the result of my research, largely from the FDA's 510K database.   (Tip--the first two digits after the K represent the year the 510K was submitted).  This chronology includes only disposable infusion pumps and excludes electronic and more sophisticated pumps.  Also, as you can see, I have not been able to include predicate device information for several devices, especially a number of early pumps.  The FDA apparently purges even summary device information after a certain number of years.  This is unfortunate and, given how long it typically takes to receive information under Freedom of Information Act requests (the only other means I am of aware of for obtaining 510K information), should be remedied as part of the CDRH's evaluation of the 510K process. 

I'm sure this chronology is incomplete, but I hope it may prove of use to others.  I considered trying to render this information by way of a diagram or other visual format, but this is beyond my current abilities.  I have, however, been thinking of an appropriate visual metaphor for the pain pump market and have come up with an Inverted Pyramid.   The earliest approved device or handful or devices are the base upon which the subsequent proliferation of new entries is founded.   The stability of such a structure is obviously dependent upon having a rock-solid base.  It seems you can have a well-developed medical device market that may have as its foundation a single original predicate device. 

I tried to make clear my concerns about the FDA's approval of I-Flow's PainBuster in a prior post.  Lacking access to 510K documents for other early devices, including those of McKinley and Breg, it's difficult to know whether such concerns are also warranted regarding these devices.  

It makes sense to me that because the 510K approval process is premised upon the concept of substantial equivalence, the Inverted Pyramid model of market development is likely to be common.  

Technical information on the differences between various types of pain pumps can be found in the article Disposable Infusion Pumps.

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Do Doctors Routinely Overdose Patients with Local Anesthetics?

The American Society of Regional Anesthesia and Pain Medicine (ASRA) recently released a Practice Advisory on Local Anesthetic Systemic Toxicity.   Systemic toxicity refers to central nervous system or cardiac effects of a local anesthetic, most often from an unintentional vascular injection.  While most of the concerns of this advisory don't have much application to pain pumps, I did find references to some articles of interest, including Upper Extremity Regional Anesthesia: Essentials of Our Current Understanding, 2008, in which Neal et al, state:

Whether increasing local anesthetic mass (mass =concentration × volume) results in a higher success rate is controversial in clinical settings. Laboratory studies clearly indicate that neural blockade requires very little local anesthetic. A variety of animal models have shown that neural blockade can be successfully accomplished with extremely small amounts of local anesthetic. For example, neural blockade occurs with only 1.6% of the total injected volume of local anesthetic, with only 0.02% lidocaine concentration within the nerve, or with local anesthetic deposited along only 3 cm of nerve length. Although these animal data represent an idealized state wherein local anesthetic is deposited directly on nerves, they suggest that anesthesiologists may well overdose local anesthetic in their clinical practice.  (citations omitted)

This is a very short passage from a lengthy article, but I found it quite thought-provoking.  What if it is, in fact, true that anesthesiologists routinely greatly overdose their patients in performing nerve blocks with local anesthetics?  It certainly raises questions about the accuracy of the drug companies' dose recommendations for drugs such as Marcaine, where the recommendation for a peripheral nerve block with the 0.50% concentration is 5 to 45 ml per dose.  If the same 1.6% figure from above is all the volume needed to produce a block, this would mean that of a 25 ml dose, only 0.4 ml would actually be necessary.  

Routine overdoses with nerve blocks may have occurred for decades (and continue to occur) because there is typically no apparent immediate harm to the patient.   One might reasonably ask, so what?  No harm, no foul--right?   With pain pumps, however, I suspect the risk of harm with an  overdose is magnified because the volume of local anesthetic is greater, especially in the first 24 hours when the flow rate is at its highest, and the drug is administered not in a single dose, but continuously (meaning the affected tissues are repeated exposed).   When the pain pump catheter is inserted in a confined space and/or under a surgical dressing which creates additional constriction, it appears that the risk of harm of the toxicity of the local anesthetic may tip over into permanent cell death.

Pain pump manufacturers would like to characterize the use of  local anesthetics with their product as equivalent to that of a nerve block.  As I've argued previously, however, continuous infusion via pain pumps represents an off-label use of local anesthetics.   Even if one accepts the pain pump makers' characterization, let's ask the same question raised in the above quote:  How much of the 65 ml infused in the first 24 hours of a 100 ml 2ml/hr pain pump is actually necessary to provide pain relief?  I strongly suspect that neither the device manufacturer, the drug company, nor the surgeon who inserts the pain pump has any idea.  

One other implication of this passage:  anesthesiologists have the greatest knowledge among physicians about the use of local anesthetics.  If the experts routinely use far too much of these drugs in their patients, what does this mean for surgeons employing them in pain pumps?  Prior to pain pumps, the experience of most surgeons with local anesthetics was likely limited to the injection of small amounts around incision sites.   Now, they are routinely using far greater volumes of these drugs than have ever before been used, including by anesthesiologists.  Is it any wonder that the number of adverse events in patients involving local anesthetics has increased dramatically following the advent of pain pumps?   

 

 

 

510(k)s, Substantial Equivalence, and Pain Pumps: Part Two

For most of the pain pumps on the market in 1999 (referred to in Part One of this post), scant information remains available online from the FDA.  However, the Summary of Safety Effectiveness for I-Flow's PainBuster under K980558 is still accessible.  In this document, I-Flow stated that the PainBuster was substantially equivalent in intended use to the Pain Control Infusion Pump (PCIP) (K896422) distributed by Sgarlato Laboratories and to the Homepump C-Series (K944692) and Homepump Eclipse (K932740) marketed by I-Flow. 

There are several interesting things about these statements of equivalence.  It was actually the Burron Ambulatory Drug Delivery System approved as K896422 and not the Sgarlato PCIP, which was K990101.  I-Flow's document did accurately state that the PCIP was produced by Burron/B. Braun.  And, K990101 does show that Sgarlato claimed equivalence to the Burron device and that Burron would manufacture the PCIP for Sgarlato.   The strange thing is that I-Flow's submission to the FDA was made in February 1998 and Sgarlato's was not made until January 1999.  On its face, therefore, I-Flow claimed substantial equivalence to a device that had not yet been submitted to the FDA for approval.  

Sgarlato's summary stated that its PCIP would be used for the same intended purpose as the Burron device.  Sgarlato's intended use was for continuous infusion of local anesthetics directly into the intraoperative site for management of postop surgical pain.  The Burron device was submitted to the FDA in 1989, however.  I am quite skeptical that it could have been approved for use as a pain pump at that time.  Unfortunately, all information about the 510(k) for the Burron device has been purged from FDA's 510(k) database. 

The other devices I-Flow claimed in 1998 as predicates were its own Homepumps.  However, both the C-Series and Eclipse pumps had much higher flow rates (up to several hundred ml/hr) and other routes of administration, including intravenous.  I-Flow claimed that the design of the PainBuster would be identical to that of the Homepump. 

In short, I-Flow claimed substantial equivalence to the Sgarlato PCIP for intended use and to its own Homepump for the components of the device.  The I-Flow PainBuster (which would be used by I-Flow as a predicate device for all of its later pain pumps and by numerous competitors for their devices in years to come) is premised upon what is known as a "split predicate."

A few weeks ago, the Center for Devices and Radiological Health at the FDA, issued extensive Preliminary Internal Evaluations of the 510(k) process.   This document contains a very useful history of the 510(k) program and a number of findings and recommendations by a working group charged with reviewing the existing process, including this finding:

"The term 'split predicate' refers to a situation in which a 510(k) submitter is attempting to 'split' the 510(k) decision-making process by demonstrating that the new device has the same 'intended use' as one predicate and the same 'technological characteristics' as another.  This practice is akin the combining different attributes of two or more devices into a single, nonexistent predicate device that may bear little resemblance to the device under review or to any marketed device.  Concerns have been raised that the use of a 'split predicate' may not allow for a valid comparison of safety and effectiveness because not such device exists, either in part or whole, and there is therefore no real world information about its risks and benefits." (p. 59)

In Part One of this post, I wrote that at some point there had to have been a step from an infusion pump intended to be used for other purposes to a pump intended to infuse local anesthetics.  It appears that I-Flow's PainBuster was one of the earliest (if not the first) of these steps.  Much of the current pain pump market has developed by making claims of substantial equivalence to I-Flow devices.  If there are serious questions about the basis of FDA approval for a threshold device like the PainBuster, those questions necessarily spread through the chains of substantial equivalence to numerous devices that have followed. 

 

 

 

510(k)s, Substantial Equivalence, and Pain Pumps: Part One

The FDA's guiding principle for approval of 510(k) submissions for new medical devices is "substantial equivalence."  An applicant is directed to use at least one previously-approved predicate device as the foundation for its application and show how the new device has the same intended use as the predicate device.  To find that a device is substantially equivalent, the FDA must determine that the new device has the same technological characteristics as the predicate device, or has different characteristics but the applicant has demonstrated that the device is safe and effective and does not raise different questions of safety and effectiveness as the predicate device. 

Once a device has been approved, it may become a predicate device for later versions of the same product or for a competitor's product.  And, each new applicant may rely on just the most recently approved devices and not the earlier generations.   For pain pumps, as an example of this process, take the Alpha Infusion Pump, manufactured by Advanced Infusion, Inc.  The most recent version of this device was approved by the FDA in 2008 under 510(k)071532.  The predicate devices listed are a prior version of the Alpha Infusion Pump, approved in 2002 under K021964, and the Help Technologies (later McKinley) Accufuser under K003915.  (The links are not to the complete 510(k)s; only summaries are available from the FDA's online database.  Earlier than 10-12 years and typically even the summaries have been purged and only the clearance letter and a brief statement of the indications for use remain).  The 2002 510(k), in turn, relies upon the initial Alpha Pump approved in October 1999 under K992551. 

What's interesting in the 1999 510(k) summary is the number of predicate devices to which the Alpha Infusion Pump claims equivalence:

"The proposed device, the Alpha Infusion Pump, claims substantial equivalence in intended use and operation to the Baxter Intermate LV Elastomeric Infusion Device (K922382) and the I-Flow PainBuster Infusion System (K980558). Both are elastomeric chamber infusion pump intended to deliver medications or fluids to a patient by an intravenous, intra-arterial, subcutaneous, or epidural route. These pumps are ambulatory, external disposable infusion pumps which deliver medication or fluids percutaneously to the patient via a catheter. They control flow rate using a flow restrictor.

The proposed device, the Alpha Infusion Pump, claims substantial equivalence in intended use to the Burron Ambulatory Drug Delivery System (K896422), the Sgarlato Laboratories Pain Control Infusion Pump (K990101), and the McKinley Medical OutBound Disposable Syringe Infusor (K982256). These infusion pumps differ from the Alpha Infusion Pump only in the method used to pressurize the medication or fluid contained within the pump.

The proposed device, the Alpha Infusion Pump, claims substantial equivalence in intended use to the McKinley Medical OutBound PCA Pain Management System (K982256) and the Breg Pain Care 2000 (K983454). These infusion systems provide for the delivery of a bolus of medication on patient demand through a percutaneous catheter."

In 1999, the pain pump market was already beginning to expand quickly and, as far as I can gather, the predicate devices listed in this 510(k) comprise most of the then existing devices.   What I'm interested in is that at some point, there had to have been a step from an infusion pump intended to be used for other purposes to a pump intended to infuse local anesthetics.   How sound was the information the FDA was relying on when it found the first pain pump to have been substantially equivalent to an infusion pump used for other purposes? How stable is the foundation of predicate devices upon which the pain pump market has been built?

 

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Infusion Pump Mechanics & the Significance of Inaccurate Flow Rates

I am working on another post relating to FDA regulation of pain pumps, but expect it may be a week or two before I am able to complete it.  In the meantime, I thought I would share an article I recently came across----Disposable Infusion Pumps by Skryabina and Dunn.  It contains useful explanations of how some of the most common types of these pumps actually function.

These devices are used for many purposes beyond that of a "pain pump"--delivering local anesthetics post-operatively at or near a surgical site.  These include the delivery of other medications, including chemotherapy, antimicrobials, antibiotics, as well as the delivery of anesthetics or analgesics by other routes, eg., continuous epidural, peripheral nerve block, and i.v..  The authors provide concise descriptions of the mechanisms of several types of non-electric pumps including elastomeric, positive-pressure (spring-powered and gas-pressured powered), negative-pressure (vacuum), and patient-controlled analgesia (PCA) pumps. 

The flow rates of medications through disposable pumps are significantly inaccurate--typically within +/-15% or even +/-20%.  (Compared to +/-3% with electronic syringe pumps and +/-5% with electronic volumetric pumps).  I believe most pain pump manufacturers include the +/-15% figures in their written materials--see, eg. the flow rate table included in the product Insert for the On-Q Pump with Fixed Flow Rate. 

Nonetheless, I assume most surgeons who use a pain pump labeled with a 2 ml/hr flow rate are likely to believe that the device delivers only 48 ml of local anesthetic in the first 24 hours.  In fact, the same flow rate table in the Insert for the On-Q Pump (along with all other documents for the On-Q I've seen) shows that a 100 ml pump will actually deliver 65 ml in the first 24 hours.  For the first several hours, the flow rate is actually 2.5 ml or higher. 

If the anesthetic is 0.50% Marcaine, 65 ml means 325 mg.  The maximum 24 hour dose for Marcaine is 400 mg and, as I've stressed before, this is based on the risk of systemtic toxicity (neurological or cardiac) and not local (tissue) toxicity.  Surgeons commonly use additional injections of local anesthetics around surgical sites during procedures.  Thus, it would take only an additional 15 ml of 0.50% Marcaine, along with a 100 ml 2 ml/hr. pump, to reach a 400 mg dose in the first 24 hours after surgery. 

I believe many pain pump manufacturers have blithely assumed that any 24 hour dose of Marcaine as long as it remains less than 400 mg, in most any part of the body, regardless of the concentration, and regardless of the route of administration (continuous infusion vs. others), is inherently safe.  For all who have sustained injuries from pain pumps caused by local anesthetic toxicity, this has been a tragically flawed assumption. 

 

FDA's Failure to Demand More of Pain Pump Makers puts Patients at Increased Risk of Harm.

I have been reviewing the FDA's regulatory scheme over pain pumps and believe I've identified several  weaknesses which are likely to adversely affect patient safety.

Pursuant to 21 United States Code 360c, medical devices are divided into three classes for purposes of regulation: Class I, General Controls; Class II, Special Controls; and Class III, Pre-Market Approval.

The pre-market approval process is rigorous and the FDA requires a device manufacturer to submit considerable documentation regarding a device’s safety and effectiveness in order to obtain approval. Understandably, device manufacturers prefer to attempt to have their devices approved as Class I or II devices.

I was surprised to find that Class III is actually the default classification. Subsection (f) of 21 USC 360c provides:

Any device intended for human use which was not introduced or delivered for introduction into interstate commerce or commercial distribution before May 28, 1976, is classified in Class III unless—

(A) The device—

(i) is within a type of device (I) which was introduced or delivered for introduction into interstate commerce for commercial distribution before such date and which is to be classified pursuant to subsection (b) of this section or (II) which was not so introduced or delivered before such date and has been classified in Class I or II, and

(ii) is substantially equivalent to another device within such type…(emphasis added)

Pain pumps are classified as Class II devices pursuant to federal regulation 21 CFR 880.5725, which covers infusion pumps and is part of the overall regulation of general hospital and personal use devices.  Class II devices are subject to special controls and for pain pumps this concerns performance standards.  A pain pump manufacturer is required to certify in its application materials to the FDA that its device meets an industry standard relating to infusion pumps.  These standards include:  1) AAMI (Association for the Advancement of Medical Instrumentation),  Draft Infusion Device Standard; 2) UL (Underwriters Laboratory) 544 Standards for safety, medical and dental equipment; and 3) IEC (International Electrotechnical Commission) 601-1/ANSI (American National Standards Institute) ES1-1985 Safe Current Limits for Electromedical Apparatus. 

I'm sure these standards are important and applicable to the safe-functioning of many types of infusion pumps. I'm also sure they're relevant to the types of adverse events in infusion pumps the FDA recently announced it was seeking to combat through tighter regulation.  (My post on this is here ).  However, most pain pumps are much less mechanically-complicated than the infusion pumps used to deliver insulin or chemotherapy drugs (to name a few types).  So, these standards really don't get at the main safety concerns with pain pumps which involve the basic threshold question of whether they are reasonably safe for their intended use of continuous infusion of local anesthetics.  As a result, I don't see the FDA's classification of pain pumps as Class II devices conferring any benefits for patient safety.

To my knowledge, all pain pump manufacturers have received approval from the FDA by utilizing the substantial equivalence provision mentioned above.  In this process, the FDA requires device manufacturers to submit a Section 510(k) Pre-Market Notification of intent to market the device. If approved, the FDA issues a letter (see example here) with the following operative language: “The FDA finding of substantial equivalence of your device to a legally marketed predicate device results in a classification for your device and thus, permits your device to proceed to the market.”

In March 1993, the FDA issued Guidance on the content of Pre-Market Notification [510(k)] Submissions for external infusion pumps. Section II D is on device description. The description is required to provide a clear statement of the intended use(s) of the infusion pump, including specifying the route(s) of administration and if the infusion pump is labeled for use with a specific drug/biologic the applicant must supply information demonstrating that use of the drug/biologic with the device is consistent with the approved drug/biologic labeling.

Pain pumps are clearly labeled for use with local anesthetics. However, as I have argued in a previous post, the continuous infusion provided by pain pumps is not an approved use of local anesthetics, especially the most commonly used—Marcaine.

For example, in its 1998 510(k) submission for its PainBuster pump, I-Flow reported that there are no specific drugs referenced in the labeling for the PainBuster infusion system, but that it is intended for use with general local anesthetics. I suspect that most, if not all, 510(k) submissions for pain pumps list only a similar general statement.

The FDA could insist that pain pump manufacturers provide evidence in their 510(k) submissions demonstrating how these devices are consistent with the uses approved in local anesthetic labeling. Manufacturers would then be forced into attempting to characterize the use of local anesthetics in their devices--continuous infusion--as akin either to local infiltration or a peripheral nerve block (PNB), which are approved uses. 

Local infiltration involves the injection of a small amount of local anesthetic, typically near a surgical site. Far too much anesthetic is delivered by a pain pump for a manufacturer to claim it is similar to local infiltration.

A PNB likely utilizes a larger amount of anesthetic than in local infiltration, but typically does not approach the volume used in a pain pump. Also, a PNB involves the insertion of a catheter at some distance from an incision site, while a pain pump catheter is intended to be inserted close to an incision. Traditionally, PNBs were accomplished with a single dose of local anesthetic. However, in recent years continuous PNBs have begun to be used by anesthesiologists. Dr. Brian Ilfeld is one of the leading researchers on this technique; here's an article by him on PNBs

It is unclear to me whether continuous PNBs are really an approved use of local anesthetics, per the manufacturers' labeling. However, the articles I’ve seen indicate a greater degree of safety than with pain pumps. I would think this has much to do with continuous PNBs being performed by anesthesiologists as opposed to pain pumps which are typically placed by surgeons. A catheter which will deliver a local anesthetic at a greater distance from a surgical site is less likely to produce wound healing problems. Also, an anesthesiologist is likely to pay closer attention to the volume of local anesthetic used in a continuous PNB than a surgeon utilizing a pain pump.

The incidence of adverse events involving pain pumps has certainly been such that much greater regulatory scrutiny is warranted. These events extend far beyond chondrolysis in shoulder surgeries.  (See my prior post).  The FDA's recently announced requirements that pain pump manufacturers and local anesthetic manufacturers must revise their product labels to highlight the risk of chondrolysis in shoulder surgeries leaves unaddressed the more basic question of whether continuous infusion is a safe use.  The FDA should require pain pump manufacturers to provide detailed evidence about why their devices are consistent with the uses approved by local anesthetic manufacturers. 
 

A Safer Alternative to Marcaine and Other Local Anesthetics?

In my last post, I discussed a 2008 research article which found a relationship (in both duration of exposure and concentration) between Bupivacaine and muscle damage.   In a prior post, I sought to summarize some earlier articles which also discuss local anesthetics and myotoxicity.  Given the significant evidence that seems to support this troubling relationship, I've wondered if there are any efforts to develop alternatives to existing local anesthetics, especially Bupivacaine.

In "Prolonged Duration Local Anesthesia With Minimal Toxicity," (2009) Hila Epstein-Barash and colleagues (which include Dr. Daniel S. Kohane, one of the authors of the above 2008 article) describe a compound which has powerful anesthetic properties but with causes little damage to human cells.  The authors explain the motivation behind their research:

The development of local anesthetics to provide prolonged analgesia from a single injection has encountered 3 principal challenges: inadequate duration of action, systemic toxicity, and adverse local tissue reaction. The purpose of this research was to produce a local anesthetic lasting many days without those detrimental sequelae.

Conventional local anesthetics are intrinsically myotoxic. They are also myotoxic when released from a wide range of delivery systems, even when the delivery systems themselves are minimally toxic. The myotoxicity of bupivacaine increases dramatically over extended durations of exposure, suggesting that myotoxicity may be an inevitable consequence of sustained release of such compounds. (citations omitted)

The article is quite technical and I don't begin to understand all of its complexities.  What I do grasp, however, is that the researchers developed a formulation called STX (saxitoxin) which is a site 1 sodium-channel blocker, which blocks nerves in a different manner than conventional local anesthetics.  Site 1 sodium channel blockers are known not to cause myo- or neuro-toxicity.  The authors were interested in providing a controlled release of STX over an extended period of time in order to attempt a prolonged nerve block, so they used liposomes--tiny bubbles made of the same material as cell membranes--as a delivery vehicle for the medication.  The authors reported that in cell cultures of rats, Bupivacaine but not STX was myo- and neuro-toxic in both time and concentration dependent manners.  The authors state these results suggest that controlled release of STX and similar compounds can provide very prolonged nerve blocks with minimal systemic and local toxicity.

I have no idea how far in the future STX might be approved and available for human use.  However, it is encouraging to know that there are scientists concerned enough about the shortcomings of Bupivacaine and other conventional local anesthetics who are working to create safer alternatives. 

 

Myotoxicity of Local Anesthetics: Implications for Pain Pumps

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.

Does New FDA Oversight Include Disposable Pain Pumps?

I am still a bit confused as to whether the new oversight regime the FDA announced yesterday applies to the disposable local anesthetic infusion surgically-implanted pumps that are my focus in this blog.

Reading the New York Times article on the announcement led me to think these devices might be excluded, as it focuses on IV-implanted, programmable devices used to provide insulin, chemotherapy, and pain medications (but patient-controlled).  There have been over 56,000 adverse events and 710 deaths involving these devices in the past 5 years.  These are truly staggering numbers.  Regarding the types of problems reported, the FDA Press Release indicates: The most common types of reported problems have been related to:

* software defects, including failures of built-in safety alarms;
* user interface issues, such as ambiguous on-screen instructions that lead to dosing errors; and
* mechanical or electrical failures, including components that break under routine use, premature battery failures, and sparks or pump fires.

Failures of infusion pumps have been observed across multiple manufacturers and pump types. The FDA says that many of the reported problems appear to be related to deficiencies in device design and engineering.

I saw nothing about shoulder chondrolysis or other injuries from local anesthetics. So far, all of this sure seemed outside the scope of pain pumps. 

The next step up in document complexity is the FDA's White Paper on its Infusion Pump Improvement Initiative.   I read  "In general, an infusion pump is operated by a trained user, who programs the rate and duration of fluid delivery through a built-in software interface" and it confirms my initial belief.   However, then among the pump mechanisms elastomeric is listed and this is one of the most common types for disposable pain pumps.  Finally, at the end of the paper I see among the footnotes:  1 This document does not pertain to implanted infusion pumps, which are surgically placed in the body.  Okay, now I'm pretty sure this significant announcement doesn't apply to the devices with which I'm familiar.  However, there are several additional documents the FDA has included and, for completeness sake, I read on.

The letter to infusion pump manufacturers from Jeffrey E. Shuren, Director of the FDA's Center for Devices and Radiological Health (CDRH) also focuses on software, design, human factors, and manufacturing problems. 

There's detailed information about CDRH's software research on infusion pumps.  I had no idea the FDA has a software engineering laboratory. 

Ultimately, there's the agency's Guidance for Industry and Staff regarding 510(k) Pre-Market Notification Submissions.  This is a draft document (34 pages in PDF form) which will be entering a 90-day comment period.  When complete it will replace the Guidance on the Content of Premarket Notification [510(k)] Submissions for External Infusion Pumps, issued March, 1993.  

My confusion was finally resolved (I think) by reading the Scope section of this document.  It makes clear that all infusion pumps addressed by 21 C.F.R. 880.5725 will be covered by the new guidelines. This includes numerous types of devices including all Elastomeric Infusion Pumps (products coded MEB), and excludes only the following: gallstone dissolution pumps (MHD), opthalmic infusion pumps (MRH), and analytical sampling infusion pumps (LZF).   Just to be sure, I double-checked the most recent 510(k) Submission for the On-Q Painbuster, which confirms the same regulation (880.5725) and product code (MEB). 

So, it does indeed look like I-Flow, Stryker and company will have to learn how to comply with considerable new requirements and provide alot of additional information in future premarket submissions to the FDA.   This is certainly good news, but I have lingering confusion because of the lack of mention in any of these new documents from the FDA of the adverse events involving these devices with which I'm familiar.   An Appendix to the Guidance document lists the following categories of "Risks to Health" with infusion pumps:  Overdose, Underdose, Delay in Therapy, Incorrect Therapy (wrong medication or correct medication but wrong dosage or infusion rate), Air Embolism, Trauma (burns, cuts, abrasions, bruising), Electric Shock, Infection, Allergic Response, and Exsanguanation.  Perhaps the numerous cases of chondroylsis and tissue necrosis are intended to be included in one of these categories (Infection? Allergic Response?). 

When I think again about the number of adverse events--56,000--reported involving all types of infusion pumps over just the last 5 years, I realize that the number involving local anesthetics, even if it's 500 or more, is likely to be less than 1% of the overall events.  Where do local anesthetic infusion pumps and the injuries they appear to cause fit into the broader regulatory and safety scheme involving this class of devices?  My initial reaction is that the problems with pain pumps don't have much to do with design, human factors, or manufacturing issues (and certainly not software).    I will certainly reserve judgment and keep an eye on how the new oversight regime takes shape.  Of course, it will also be interesting to see how these developments may affect litigation involving injuries and deaths from PCA and other programmable pumps.  I can envision claims which were initially viewed as malpractice expanded to also (or instead) focus on the liability of the pump manufacturer. 


 

 

 

Why a Pain Pump is not a Syringe.

I recently came across a post by Armand Rosetti which summarized some news articles relating to I-Flow Corporation and its Chief Executive, Donald Earhart. Especially interesting are some statements Mr. Earhart made in a November 5, 2008 conference call with investment analysts regarding the company’s third quarter earnings.  Earhart was answering questions regarding the status of the shoulder chondrolysis lawsuits, and said:

I’ve said this argument before on the conference calls, is that a pain pump or a delivery device, whether it be a syringe or one of our pumps delivering a drug, how do you blame the device, because there’s no way the device can cause the disappearance of cartilage. It would have to be whatever is delivered into the site or would have to be the technique by the doctor or would have to be the sutures or it would have to be the staples or it would have to be something else used during the surgery, but it can’t be our pump, because our pump can’t cause cartilage to disappear…. It’s like using a syringe to deliver a narcotic. We can’t be held responsible for the side effects, if I’m the syringe manufacturer, of the drug.

This raises an important point.  Clearly, it is the toxicity of the local anesthetic that causes the direct harm to the patient--whether the result be the destruction of shoulder or other joint cartilage, tissue necrosis around a surgical site, or other injury.  How then can a plaintiff reasonably seek to blame the maker of the device and not the drug?  Because a pain pump manufacturer retains a legal responsibility to patients to provide that their devices may be safely used with local anesthetics in a manner intended by the manufacturer of the local anesthetic.  Continuous infusion through a pain pump is not a listed intended use of a local anesthetic; it is an off-label use.   A statement such as I-Flow makes in its current Directions for Use for the On-Q pump, “medications or fluids must be administered per instructions provided by the drug manufacturer,” has little meaning when the use in question is not addressed by the manufacturer. 

Mr. Earhart and I-Flow appear to take for granted that continuous infusion is no different than the uses approved by the local anesthetics manufacturers. I contend pain pumps represent a categorically different use both because of the larger volume of local anesthetic infused and the significantly greater duration of exposure of the affected tissues to the medication. For example, a single bolus dose of 100 mg (20 ml) of Marcaine to produce a nerve block may well create less risk of local tissue toxicity than continuously infusing smaller volumes—2ml/hr—but with a larger total volume 240 mg (100 ml) over a much longer time—2-5 days.

On the other hand, the uses to which a syringe is put--—local infiltration around a surgery site and injections to produce various types of nerve blocks—are approved uses by the drug manufacturer.  Because there are a variety of known risks of patient injury with their devices, pain pump manufacturers have a duty  to timely and adequately convey warnings of such risks to the physicians who use them.