Letters to the Editor:
On the Withdrawal of Rapacuronium by the FDA
"Polypharmacy" Pain Pump Infusing Clonidine Can Confound Anesthesia Care, Challenge
Australian Regulations Control Office Anesthesia
JCAHO May Threaten Patient Safety
To the Editor:
I read with interest the recent Anesthesiology editorial1 and accompanying articles2-4 regarding serious bronchospasm due to rapacuronium and the withdrawal of rapacuronium by the U.S. Food and Drug Administration (FDA). This makes rapacuronium the twelfth medication or vaccine to be withdrawn by the FDA since 1997. The others are: Duract, Hismanil, Lotronex, Pondimin, Posicor, Propulsid, Redux, Seldane, Raxar, RotaShield, and Rezulin. Such a record hardly inspires confidence in the FDA's screening of new medications.
It is important to note that when a new medication is first marketed, it is still in phase IV of development and testing. Thus, the first patients to take a newly released medication are, in a sense, still participating in the research and development process although they are usually unaware of this.5 These patients need our protection.
Prior to marketing, a new medication has usually been studied in a relatively small number of patients or subjects having limited coexisting diseases and who are taking few concurrent medications.5 After release, however, more patients, who have a variety of concurrent medical conditions and who take various other medications generally use the new drug, It is therefore after release that the side effects of a new medication will often become known.
For these reasons, and in view of the FDA's poor record of screening new medications, Sidney Wolfe wisely recommends that new drugs should not be used until they have been on the market for five years. He terms this the "five-year rule."6 I feel that anesthesiologists should adopt this rule to protect their patients.
Mitchel B. Sosis, M.D., Ph.D.
(MitchelSosis@hotmail.com)
Acting Director of Anesthesiology
Campus Eye Group
Hamilton Square, NJ
References
1. Goudsouzian NG: Rapacuroniurn and bronchospasm. Anesthesiology. 2001;94:727-8.
2. Kron SS: Severe bronchospasm and desaturation in a child associated with rapacuronium. Anesthesiology. 2001;94:923-4.
3. Naguib M: How serious is the bronchospasm induced by rapacuronium? Anesthesiology. 2001;94:924-5.
4. Meakin GH, Pronske EH, Lerman J, Off R, Joffe D, Savaree AM, Lynn AM: Bronchospasm after rapacuroniurn in infants and children. Anesthesiology. 2001;94:926-7.
5. Berkowitz BA., Katzung BG: Chapter 5: Basic & clinical evaluation of new drugs, In: Katzung BG (Editor): Basic & Clinical Pharmacology, 7th Ed., Appleton & Lange, Stamford, CT. 1998. pp 62-72.
"Polypharmacy" Pain Pump Infusing Clonidine Can Confound Anesthesia Care, Challenge top
To the Editor:
An intriguing case occurred recently at our hospital. This case involves resistant hypotension refractory to treatment in a patient under general anesthesia with an implantable intrathecal device. This polypharmacy intrathecal pump was in place for pain control. The patient was scheduled for a revascularization of the lower extremities (aorto-bifemoral artery revascularization). The patient was an obese female with COPD, HTN, chronic pain, and peripheral vascular disease. The pain pump contained fentanyl, meperidine, bupivicaine and clonidine.
Intra-operatively, the patient appeared to have a high output, low SVR/PVR clinical state that was unresponsive to Neosynephrine, dopamine, epinephrine and norepinephrine. This patient reacted as if she was adrenergically nonresponsive or catecholamine depleted. Over the next sixteen days, the patient continued with this high cardiac output, low SVR/PVR state despite having a continual Levophed infusion. Ultimately the patient succumbed to multiorgan failure and respiratory complications. The differential diagnosis list was logically worked out with consults and labs. Briefly, cardiomyopathy and heart related problems ruled out, sepsis early on (she had catheter tip positive cultures 9 days post-op) ruled out, neuromuscular/spinal related catastrophes ruled out, endocrine problems ruled out, limb ischemia /lactic acidosis ruled out. Submucosal intestinal ischemia was never ruled out, but for it to have been a problem intra-operatively and continue for 3 weeks without becoming obvious on blood gases is unlikely.
This letter is to warn others of the potential problems with intrathecal pumps, specifically ones with alpha 2 agonist medication.
Studies have shown the hypotensive side effect of clonidine in whatever route given.1-14 The clonidine dose used on this patient was on the low end, 55 micrograms a day. Some studies discuss high doses of 500 micrograms a day.15 No studies have investigated the neuromuscular, vascular or cardiovascular physiologic changes that can occur over long period of administration.
What's the price of pain control? At what point do we say, turn it offÑbecause it's all investigational. This mode of pain control is becoming more popular, and we all will encounter more such patients needing general and/or regional anesthesia. All I can say is it may be prudent to learn more about intrathecal drugs, their side effects, how to avoid side effects, how to turn the pumps off safely without withdrawal phenomenon and what the physiology behind long- and short-term effects of intrathecal clonidine.
Kyle Jones, MD
Gurley, AL
References
1. Chiari A,Christine L, Eisenach J., et al :Analgesic and Hemodynamic effects of intrathecal clonidine as the sole analgesic agent during first stage labor. Anesthesiology. 1999;91:388-396.
2. Kock M, Gautier P, Pavlopoulou A, et al: Epidural Clonidine or Bupivicaine as the sole analgesic agent during and after abdominal surgery. Anesthesiology. 1999;90:1354-1362.
3. Eisenach JC, Lysak SZ, Viscomi CM: Epidural clonidine analgesia following surgery: phase 1 Anesthesiology. 1989 Nov;71(5):640-6.
4. Eisenach JC, Lavand'homme P, Tong C, Cieng JK et al: Antinociceptive and hemodynamic effects of a novel alpha2-adrenergic agonist. Anesthesiology. 1999 Nov;91(5): 1425-36.
5. Dobrydnev IL, Tsygankova 01: Clinical experience in the use of clonidine in regional anesthesia and early postoperative period (1984-1989). Anesteziol Reanimatol. 1999 May-Jun;(3):4-12.
6. Ongioco R, Richardson CD, Rudner XL, Stafford-Smith M, Shcwinn DA. Alpha2 adrenergic receptors in human dorsal root ganglia: predominance of alpha 2b and alpha 2c subtype mRna. Anesthesiology. 2000 Apr; 92(4):968-76.
7. Khan ZP, Ferguson CN. Jones RM. Alpha-2 and imidazoline receptor agonists. Their pharmacology and therapeutic role. Anaesthesia. 1999 Feb; 54(2):146-65.
8. Grubb MC, Stornetta RL, Pence R, et al: Antagonist precipitated clonidine withdrawal in rat: effects on locus coeruleus neurons, sympathetic nerves and cardiovascular parameters. J Anton Nerv Syst. 1998 Jul 15;71(2-3):85-95.
9. Del Carmen Garcia M, Enero MA, Celuch SM: Hypotensive and Hypertensive effects of catecholamines intrathecally injected in anesthetized rats. J Auton Nerv Syst. 1996 Jun 10;59(1-2):1726.
10. Gautier P, Kock M, Luc F, et al: Intrathecal clonidine combined with sufentanil for labor analgesia. Anesthesiology 1998;88:651-656.
11. Kimsha W, Chiari A, Krafft P, et al: Hemodynamic and analgesic effects of clonidine added repetitively to continuous epidural and spinal blocks. Anesthesia & Analgesia. Vol 80:322-327.
12. Kital T, Kagawa K, Mammoto T et al: Supraspinal not spinal alpha 2 adrenoceptors are involved in the anesthetic sparing and hemodynamic stabilizing effects of systemic clonidine in rats. Anesthesia & Analgesia. 2000:90:722-726.
13. Benhamour D, Thorin D, Brichant IF et al: Intrathecal clonidine and fentanyl with hyperbaric bupivicaine improves analgesia during cesarean section. Anesthesia & Analgesia Vol 87:609-613.
14. Mercier F, Donnas M, Bouaziz H et al: The effect of adding a minidose of clonidine to intrathecal sufentanil for labor analgesia. Anesthesiology. 89:594-601, 1998.
15. Current Practices in intraspinal therapy, evidence based review of the literature on intrathecal delivery of pain medication, clinical guidelines for intraspinal infusion: report of an expert panel, future directions in the management of pain by intraspinal drug delivery: Special Section Polyanalgesic Consensus Conference 2000, Journal of Pain and Symptom Management 2000:20(2):sl-s50.
Australian Regulations Control Office Anesthesia top
To The Editor:
Many readers of the APSF Newsletter would be aware of the New South Wales Anaesthesia Mortality Study, which has just completed its 40th year of reviewing deaths in association with anaesthesia.
For the benefit of those yet to visit Australia, New South Wales (NSW) is our most populous State (approximately 6.5 million), and its capital, Sydney, our biggest and brightest city.
After reading the Newsletter devoted to safety in Office-Based Anesthesia (OBA), our Committee thought it might be useful to describe the relevant regulatory framework existing in NSW.
General anaesthesia may only be administered here in premises which have been licensed under the Private Hospitals Act, which lays down strict requirements for equipment and staffing. Essentially these differ very little from the licensing rules for Day Surgery facilities, so that the "office" would have to be a very elaborate one indeed to qualify. A breach of this Act by any practitioner could result in deregistration (revocation of licensure) for unprofessional conduct.
Combined with the statutory duty to report all deaths occurring within 24 hours of anaesthesia or sedation for a procedure to a Coroner, the barrier to inappropriate practices in anaesthesia or sedation/endoscopy is quite formidable. So strongly is this true that the Committee classified its last death in a dental surgery as long ago as in 1986, in a case in which the operator was the sole professional person present. To some extent, the present regulations were triggered by this catastrophe.
We would agree with your correspondents on the need for tight regulation of OBA and equally strong or similar controls for "sedation" by non- anesthesiologists. The NSW laws define sedation as being a state in which the patient is still capable of responding intelligibly to a verbal message - anything less responsive than that condition is considered to be general anaesthesia, and is subject to the same strictures which govern that more involved status.
PS: Full text of the above legislation can be provided if desired (requests to: lyn@anae.rpa.cs.nsw.gov.au)
Professor Ross Holland
NSW Special Committee Investigating Deaths Under Anaesthesia
Camperdown, NSW, Australia
Danger in Fentanyl Shortage top
To the Editor:
Below is a description of a case which occurred recently at a freestanding In-Vitro Fertilization (IVF) clinic. The purpose of this report is to describe a medication error which occurred as a result of the recent shortage of a common anesthetic medication, and once again to emphasize the importance of checking labels prior to administering any medication. We are providing this case report in response to a request for reports of medication errors which appeared in the Spring 2001 APSF Newsletter.
For approximately five years, our department has provided anesthesia staffing to a freestanding In-Vitro Fertilization (IVF) clinic that is located approximately 1/2 mile from the hospital. This clinic offers full service fertility care, including anesthesia for TransVaginal oocyte Aspiration (TVA). This procedure is usually quite uncomfortable for patients, and for this reason, sedation is provided by an anesthesiologist. Typically, patients receive a combination of fentanyl, midazolam and propofol. Most patients require deep sedation. The majority of patients breathe spontaneously throughout the procedure, though at times, controlled ventilation is required.
Patients are routinely given prescriptions by the OB/GYN attendings for one vial, 2 cc, of midazolam (5 mg/cc), one ampule, 5 cc, of fentanyl (50 µg/cc), and one vial, 20 cc, of propofol (10 mg/cc). These prescriptions are filled by the individual patients at a local pharmacy. Then, the patients bring these medications to the clinic to be administered by the anesthesiologist. All emergency drugs are provided by the facility.
The case reported here involves a healthy patient with no medical history and an anesthesiologist who was given the assignment to work at the clinic approximately once every 2 months. On that day, the patient brought her own medications to the anesthesiologist in the same fashion as has been done for many years. However, on this occasion, the pharmacy substituted a 5 cc ampule of sufentanil (50 µg/cc) instead of a 5 cc ampule of fentanyl (50 µg/cc). This was done via telephone consent by the ordering OB/GYN attending who was told that this substitution was being made due to a national shortage of fentanyl.
The anesthesiologist was never made aware of this change. An assumption was made that nothing had changed over the past five years or on that day. Due to the similarity in packaging and spelling, the Sufenta (Janssen Pharmaceutical) ampule was mistaken for the typical 5 cc Sublimaze (Janssen Pharmaceutical) ampule by the anesthesiologist, and the patient was unintentionally given one cc (50 µg) of sufentanil rather than 50 µg of fentanyl.
Predictably, the patient became apneic, bradycardic and was difficult to ventilate. Fortunately, the OB/GYN physician was present to witness the anesthesiologist's concern, and he offered the information that some patients were being given a "different medication" than usual due to a "shortage" of fentanyl. Given this information, the anesthesiologist quickly identified the Sufenta vial, recognized the medication error, and immediately controlled the patient's ventilation via a bag-valve-mask system. The patient required no muscle relaxants or endotracheal intubation. The blood pressure and oxygen saturation remained normal throughout, and no medications were required to treat the sinus bradycardia. Had this medication error not been immediately discovered, the anesthesiologist may have misinterpreted the patient's chest wall rigidity from Sufenta as being laryngospasm or severe bronchospasm. This could have led to unnecessary and potentially harmful pharmacotherapy and airway management techniques.
The patient's procedure eventually proceeded uneventfully; however, she had an unanticipated prolonged stay in the clinic's PACU and was treated with intravenous naloxone only after spontaneous respirations had begun. Fortunately, there was no long-term morbidity associated with this episode.
Howard Denenberg, MD
Associate Professor and Associate Residency Director
Mordechai Bermann, MD
Assistant Professor and Director of Human Simulation Laboratory
Department of Anesthesia
UMDNJ - Robert Wood Johnson Medical School
New Brunswick, NJ
JCAHO May Threaten Patient Safety top
To the Editor:
Recent institutional policies devised to address (perceived) accreditation standards may actually lead to disaster. Two issues were a major focus during our recent accreditation survey. In California, many hospitals have removed patients' names from operating room scheduling boards. In the name of patient confidentiality, the full name has been replaced by first name only, initials, social security number or another scheme. Many anesthesiologists, nurses and surgeons believe this is both unnecessary and potentially catastrophic.
Of greater concern are policies that demand anesthesia carts and supplies be locked in areas such as obstetrics where immediate access to equipment and agents is an unquestioned absolute need. Within the secure confines of the operating room, non-controlled medications must be secured and out-of-view because of the concern that unlicensed personnel such as scrub technicians, anesthesia workroom, and custodial staff represent a tampering risk. Securing agents at the end of each case distracts attention from the patient and hinders immediate access in the rare but critical instances when they are needed. Most importantly, anesthesiologists should take the lead in speaking out against the adverse profiling (suggested by the negative assumptions and suspicions) of these full-time and dedicated employees with whom we work.
Accreditation organizations, such as the JCAHO, state that their standards do not require these draconian policies. Their consultants and surveyors demand otherwise. I call on the APSF to take the lead in determining whether such policies are indeed dangerous.
Martin Bogetz, M.D.
Medical Director, UCSF Surgery Center
Professor of Clinical Anesthesia
University of California, San Francisco