Dept Of Anesthesiology & Critical Care, University Of Pennsylvania School Of Medicine

Iatrogenic air embolism

In a recent letter to the editors of Anesthesiology, John Benumof pleads for recognition that externally pressurized blood reinfusion bags are a predicable and preventable cause of fatal air embolism (Anesthesiology 2007;207:851).  He notes that many brands of blood salvage bags require the entry of 80 plus ml of air and that the final amount of air in the bag can be much higher.  He personally has reviewed 8 fatalities in the past 10 – 12 years related to pressurizing recovered blood.  He relates the basic scenario as follows: “multiple bowls of salvaged blood were processed without purging air from the reinfusion bag, the reinfusion bag was externally pressurized {to increase flow}, there was a sudden cardiac arrest within 1 minute of the reinfusion bag being emptied of blood, there was a failed resuscitation attempt (including aspiration of air from central veins), and the autopsy showed a heart filled with air.”  He opines that reinfusion blood bags that have been filled with salvaged blood should never be externally pressurized.

David S. Smith, M.D., Ph.D.

What is six sigma? How does it apply to health care?

There are two meanings 1) Sigma ( σ ) is the accepted symbol for 1 standard deviation from the mean of the “normal” distribution (bell curve).  Since 1 sigma would exclude 31.8% of a normally distributed event under consideration and three sigma would exclude 0.3%, six sigma implies events of very low frequency (on the order of 3 per million). 2) Six sigma is also commonly used as the name of a process of quality control originally developed at Motorola Corporation and later adopted by many including General Electric Company (a six sigma error rate is considered to be virtually flawless).  In many industries application of the methodology has reduced defects, improved customer satisfaction, and decreased costs.  With respect to medicine, Parker et al used these techniques to develop a process that improved adherence for antibiotic prophylaxis in patients undergoing cardiac surgery (1); Women and Children’s hospital of Charleston used six sigma to enhance access to care by decreasing time to appointment and waiting time to see a doctor, increase patient satisfaction, and improve revenues in a resident run obstetrics and gynecology clinic (2); and Massachusetts General Hospital avoided the addition of an additional shift for its proton beam facility by changing how it scheduled cases requiring anesthesiologists (3).  Key to the success of this methodology is the fact that it is data driven.  It focuses on process improvement and variation reduction using the paradigm of define, measure, analyze, improve, and control (4).  It can be applied to both existing and planned processes.  We do not like to consider our practice of medicine to be the same as manufacturing super soaker recreational water guns.  However for success both require the correct application of a sequence of steps.  In the case of medicine  failure of any one of those steps may lead to patient injury, patient or family dissatisfaction or increased costs in the form of a cancelled case, increased hospital stay, etc.

1)      Parker BM et al: Six sigma methodology can be used to improve adherence for antibiotic prophylaxis in patients undergoing cardiac surgery.  Anesth Analg 2997:104:140-6

2)      Calhoun BC: Six-sigma inspired workflow redesign enhances access to care and increases patient satisfaction, visits, and revenues in obstetrics and gynecology residency clinic.  (http://www.innovations.ahrq.gov/content.aspx?id=1868 )

3)      Krasner J: New medicine for what ails hospitals.  Boston Globe January 28, 2008 (http://www.boston.com/business/healthcare/articles/2008/01/28/new_medicine_for_what_ails_hospitals? )

4)      Sivy J: Six Sigma.  Carnegie Mellon Software Engineering Institute Software Technology Roadmap (http://www.sei.cmu.edu/str/descriptions/sigma6_body.html )

David S. Smith, M.D., Ph.D.

Anoxic Encephalopathy; anesthesiologists still involved

The Pennsylvania Patient Safety Authority summarizes 3 years of submitted reports related to anoxic encephalopathy in Pennsylvania Hospitals (http://www.psa.state.pa.us/psa/lib/psa/advisories/v5n1march_2008/mar_2008_v5_n1.pdf ), pages 34 - 35.  Thirty one reports were identified.  Seventeen of the 31 patients died.  Nineteen appeared to be associated with the perioperative period with 4 occurring in the OR.  The PSA emphasizes that anoxic encephalopathy can be associated with more then just airway and ventilation; three occurred in association with blood loss.  The following causes were noted: BIPAP came off, arrest following sedation on the floor, arrest during OR intubation, arrest on induction of anesthesia, post extubation arrest at the end of operation, arrest following sedation in MRI, difficult reintubation in an ICU, and propofol syndrome, among others.  Eight of the 31 incidents were related, in some way, to airway management.  When one considers the total number of patients cared for in Pennsylvania hospitals during this time period, the incidence is very low, however each one had a devastating effect on the families of these patients and most likely on the caregivers involved.  Dr. Fleisher notes that “while some have argued that we approach six sigma in terms of cardiac arrests and deaths directly due to medical error, we must continue to learn from these events in order to provide the best possible care for our patients.”

David S. Smith, M.D., Ph.D.

Dr. Fleisher is Chair of Anesthesiology and Critical Care, University of Pennsylvania

There is an increased methadone use for pain therapy; there is a marked increase in methadone related deaths. Are they related?

According to one of my pain therapy sources, methadone, which is longer acting and does not cause euphoria compared to other narcotics, is increasingly being used for the treatment of chronic pain.”  However there now appears to be an increase death associated with methadone use.  According to a recent Philadelphia Inquirer article (April 18, 2008), death of people taking methadone is increasing at a very rapid rate.  According to the National Center for Health Statistics the number of methadone deaths across the United States rose from 786 in 1999 to 4,462 in 2005.The Inquirer notes that the drug is easily diverted to the black market.  They state that even though methadone does not produce a “high” it is often combined with other drugs.

            Methadone has been recently associated with cardiac death in patients using this drug.  Chugh et al (1) over a four year period prospectively evaluated all patients who had sudden cardiac death and underwent investigation by the medical examiner in the metropolitan area of Portland.  Case subjects had a therapeutic blood level of methadone and these were compared to patients with no identified methadone.  Patients with recreational drug use or any drug overdose were excluded.  They found a total of 22 sudden cardiac death cases with therapeutic levels of methadone.  The most common indication for methadone use was pain control.  They found that significantly fewer of the patients taking methadone had a structural abnormality that would explain the cardiac death compared to the non methadone group.  They speculated that death in the methadone cases may have been related to an arrhythmia.  Others (2) have suggested that methadone may produce potassium ion channel blockade, prolonged QT interval and the potential for a Torsade de Pointes arrhythmia.

            The UPENN chief of pain medicine provides the following additional information: most experts believe that methadone-related deaths are attributable to 2 main issues.  First, methadone is used by relatively inexperienced clinicians who do not understand proper dosing.  In these patients, either the initial dose is too high, or dose changes are made too frequently, and the patient "over shoots" the proper dose and then experiences opioid-induced respiratory compromise.  Second is the rarer risk of Torsade de Pointes.  This appears to be an adverse event unique to methadone among the potent opioids.  Methadone appears to block the rapid component of the delayed rectifier potassium current in a dose-dependent fashion, and as a result may prolong the QT interval.  This effect is most commonly observed in patients taking high-dose methadone (> 100 mg/day), but has been reported at lower doses.  The good news is that QTc intervals of 500 msec or more are predictive of an increased risk for Torsade de Pointes.  One of our pain doctors obtains an ECG on patients on methadone if their daily dose is > 80 mg.

            With respect to methadone there is a large inter-individual variability and that reaching a steady state can take 7 days or more.

1)      Chugh SS et al: A community based evaluation of sudden death associated with therapeutic levels of methadone.  Am J Med 2008;121:66-71

2)      Maremmani I et al: QTc interval prolongation in patients on long-term methadone maintenance therapy.  Eur Addict Res 2005;11:44-49

David S. Smith, M.D., Ph.D.

An argument for NOT stopping antiplatelet drugs prior to surgery

The Anesthesia Pain Service Guidelines presented earlier call for stopping clopidogrel seven days prior to surgery if neuraxial anesthesia is desired.  It is important to note, however, there have been a number of reported cases of coronary artery occlusion in patients with drug eluting stents after temporary cessation of either aspirin or clopidogrel.  Bengeri (1) and Bolsin et al (2) argue that the risks of cessation outweigh the risk of increased surgical bleeding and that these antiplatelet drugs should be continued into the perioperative period.  Bolsin notes that they surveyed 24 patients with drug eluting stents who presented for a total of 43 non-cardiac surgery procedures.  On 15 occasions clopidogrel was stopped though aspirin was continued.  Three patients experienced myocardial infarction secondary to in-stent thrombosis.  Two of the three infarcts occurred prior to surgery.  Only one patient of the 24 experienced excessive bleeding.

            The American College of Cardiology/American Heart Association joint guidelines for reducing the risk of a perioperative cardiac event (3) emphasized the need to continue anti-platelet drugs perioperatively.  The cases presented by Bengeri and by Bolsin et al together with the recommendations found in the ACC/AHA guidelines force the conclusion that antiplatelet drugs should not be discontinued prior to surgery in patients receiving these drugs after coronary stenting.  The Anesthesia Pain Service notes that epidural analgesia can be safely provided to patients taking aspirin.  In patients on clopidogrel, the drug should be continued preoperatively but epidural analgesia should not be offered.

1)      Bengeri S: Successful management of patients with a drug-eluting coronary stent presenting for elective surgery (letter).  BJA 2007;98:841-8

2)      Bolsin S et al: Comment on Bengeri 2007 (letter): BJA 2007;98:842

3)      Fleisher LA et al: ACC/AHA 2007 guidelines on perioperative cardiovascular evaluation and care for non cardiac surgery. http://circ.ahajournals.org

David S. Smith, M.D., Ph.D.

Package insert warnings for anti platelet or anticoagulant drugs

The package insert for Lovenox brand enoxaparin contains a black box warning about the association of this drug and hematomas after spinal or epidural anesthesia.  They note that the risk is increased by the presence of indwelling epidural catheters for analgesia, the presence of additional drugs that affect hemostasis such as NSAIDS or platelet inhibitors, and traumatic or repeated spinal or epidural puncture.  The package insert for Plavix brand clopidogrel contains no specific warnings about the concomitant use of this drug and regional anesthesia however it does warn that if a patient is to undergo elective surgery and an antiplatelet effect is not desired than clopidogrel should be discontinued five days prior to the procedure.

David S. Smith, M.D., Ph.D.

Orthopedic surgery, DVT prophylaxis and regional anesthesia

Orthopedic surgery is associated with a high incidence of thromboembolism and orthopedic surgeons have been among the most aggressive with respect to DVT prophylaxis.  Traditionally anesthesiologists have viewed many orthopedic surgery procedures as “perfect” for regional techniques such as spinal or epidural anesthesia.  Rowlingson et al is optimistic about the continued use of regional anesthesia in orthopedic patients who are receiving LMWH.  They note that “the key to optimizing patient safety however, depends on a careful calibration of the total daily dose and the timing of the first and subsequent doses of LMWH with the timing and management of the regional anesthetic procedure.”  I am not convinced that this degree of coordination and cooperation is possible particularly given the consequences (paralysis).  Dr. Richman at Penn Presbyterian Medical Center notes that most of their orthopedic surgeons use LMWH for post operative DVT prophylaxis and that patients receiving LMWH never get epidural anesthesia.  For knee surgery the anesthesiologists are using femoral nerve catheters sometime in combination with PCA.  They are willing to do spinal anesthesia as long the LMWH is not started until after surgery.  He notes that most of their orthopedic surgery patients receive general anesthesia (personal communication).

            

REF: Rowlingson JC, Hanson PB: Neuraxial anesthesia and low-molecular-weight heparin prophylaxis in major orthopedic surgery in the wake of the latest American Society of Regional Anesthesia Guidelines.  Anesth Analg 2005;100:1482-8

David S. Smith, M.D., Ph.D.

The American Society of Regional Anesthesia guidelines for regional anesthesia/analgesia when anti platelet or anticoagulants are being used

The American Society of Regional Anesthesia has taken a leadership position in defining the role of the regional anesthesia in the presence of various and changing forms of anticoagulation.  Their first consensus conference was in 1998 and the 2nd in 2003.  Conclusions from the 2nd conference often differed from those of the 1998 conference mostly because of increasing experience. Antiplatelet medications: Neuraxial regional anesthesia and NSAIDs – no contraindications, d/c clopidogrel 7 days in advance.  Unfractionated Heparin S.Q.: No contraindications, consider delaying heparin until after block if technical difficulty is expected.  Unfractionated Heparin I.V.: Heparinize 1 hr after neuraxial technique, remove catheter 2 – 4 h after last heparin dose.  LMWH, twice daily dosing: Do not start until 24 h plus after surgery, remove neuraxial catheter 2 h before first LMWH dose.  LMWH, single daily dosing:  Give first dose 6+ h after surgery, second dose 24+h after the first dose.  Neuraxial catheter may be safely maintained, catheter removed 10 – 12 h after LMWH and 2- 4 h prior to next dose; postpone LMWH if block placement is traumatic.  Warfarin: Document normal INR after discontinuation of drug (prior to neuraxial technique); remove catheter when INR < 1.5.  Note that at present the UPHS Anesthesia Pain Service is more conservative with respect to LMWH and Neuraxial blocks.  Note that data from Europe with respect to LMWH and Neuraxial complications may not approximate the United States experience as the dosing regimens have been proven to be significantly different with respect to the degree of anticoagulation.

            The major concern for regional anesthesia in the presence of anticoagulation is related to bleeding into the subdural or epidural space and resulting paraplegia.  However peripheral blocks may also be associated with hematoma formation.  The consensus conference document reviewed several reported cases.  In the cases they reviewed the neurologic deficits associated with peripheral bleeding resolved within 6 – 12 months.  The reported cases of bleeding occurred with psoas compartment or lumbar sympathetic block.  In some cases the bleeding was detected because of a fall in hemoglobin and not neurologic changes.

REF: Horlocker TT et al: Regional anesthesia in the anticoagulated patient: defining risks (the second ASRA consensus conference on neuraxial anesthesia and anticoagulation).  Regional Anesth Pain Med 2003;28:172-197

David S. Smith, M.D., Ph.D.

Anti Coagulants And Neurologic Complications

Epidural hematomas in patients on LMWH --

            Chan and Bailin (1) report the formation of a spinal epidural hematoma 3 days after a lumbar puncture in an 80 year old woman who presented with a hip fracture.  Her pre op medications included aspirin 81 mg QID and her pre op INR was 0.9.  Three attempts were required for the lumbar puncture and the CSF was initially blood tinged.    On the first post operative day she was started on SQ enoxaparin, 30 mg BID.  On the afternoon of the third post operative day she complained of low back pain together with weakness and numbness of the right upper and lower extremities.  A CT scan was negative for bleed or infarct.  Her aspirin was restarted.  She later complained of increasing bilateral lower limb numbness, with some changes on her neurologic exam including decreased DTRs some decreased LE strength and decreased sensation to touch.  She was started on IM ketorolac 30 mg for pain.  On the fourth post op day she had lost sensation below the umbilicus and was unable to move either lower extremity.  An MR showed a T12 – L3 epidural hematoma with acute cord compression.

            SreeHarsha CK et al (2) report that following epidural analgesia a patient developed a spinal hematoma that caused acute paraplegia.  The patient was a 78 year old woman admitted for total knee replacement.  The surgery was done with combined spinal and epidural analgesia at L2 – L3.  The epidural catheter was left in for post operative pain control.  The patient was placed on LMWH 10 hours after surgery (10 mg SQ) and she received a second dose 12 hours later.  The patient tested positive for occult blood in the stool and the LMWH was stopped. On the 2nd postoperative day she complained of severe back pain with was treated with oral analgesics.  Two hours later she complained of difficulty moving her lower extremities.  Exam revealed complete motor paralysis of both lower extremities and decreased sensation below L1.  An MRI showed a linear mass consistent with an epidural hematoma extending from T10 – L3.

            Aharma S et al (3) reported a thoracic hematoma after placement of a high epidural catheter in anticipation of cardiac surgery.  The 60 year old patient had been on LMWH (enoxaparin 40 mg SQ QD) and the catheter was placed 10 hours the last LMWH dose.  Five hours after catheter placement the patient complained of backache and was given oral acetaminophen.  The following morning the patient complained of weakness in both lower extremities.  MRI showed an extradural hematoma extending from T1-T4.

            In this final example, Varitimidis reported an epidural hematoma that appeared to be associated with epidural catheter removal.  The patient was a 68 year old man who presented for total knee replacement which was done using epidural anesthesia (uncomplicated placement).  The epidural catheter was left in for post operative analgesia.  Six hours after surgery LMWH (tinzaparin sodium containing 4500 IU of anti factor Xa) was injected SQ into the abdominal wall and continued with a once daily injection.  The epidural catheter was removed on the third post operative day, 12 hours after the daily dose of LMWH.  The following day (post operative day 4) the patient started complaining of muscle weakness and low back pain.  This progressed to loss of bowel and bladder function.  An MRI 26 hours after the first symptoms showed an epidural hematoma extending from T12 – L3.

1)      Chan L, Bailin MT: Spinal epidural hematoma following central neuraxial blockade and subcutaneous enoxaparin. J Clin Anesth 2004;16:382-385

2)      SreeHarsha CK, Rajasekaran S, DhanasekaraRaja P: Spontaneous complete recovery of paraplegia caused by epidural hematoma complicating epidural anesthesia: a case report and review of the literature.  Spinal Cord 2006;44:514-517

3)      Sharma S et al: Epidural hematoma complicating high thoracic epidural catheter placement intended for cardiac surgery.  J Cardiothor Vasc Anesth 2004;18:759-762

4)      Varitimidis S et al: Epidural hematoma secondary to removal of an epidural catheter after a total knee replacement.  J Bone Joint Surg Am  2007;89:2048-50

Epidural hematomas in patients on clopidogrel (plavix) –

            Unlike LMWH, I was not able to find isolated case reports of epidural hematomas associated with clopidogrel and an anesthetic intervention.  However, I was able to find several case reports of clopidogrel together with LMWH that were associated with epidural hematomas after spinal-epidural or spinal anesthesia (1,2).  I also found three reports of spinal hematoma formation in patients taking clopidogrel who had not received spinal or epidural needle insertion (3,4,5).

1)      Litz R, Gottschlich B, Stehr SN: Spinal epidural hematomas after spinal anesthesia in a patient treated with clopidogrel and enoxaparin.  Anesthesiology 2004;101:1467-70

2)       Tam NLK, Pac-Soo C, Pretorius PM: Epidural hematoma after a combined spinal-epidural anaesthetic in a patient treated with clopidogrel and dalteparin.  BJA 2006;96:262-5

3)       Steet RCS et al: Spontaneous epidural hematoma presenting as cord compression in a patient receiving clopidogrel.  Eur J Neurol  2005;12:811-813

4)       Sung JH et al: Clopidogrel-induced spontaneous spinal epidural hematoma.  J Korean Med Sci 2007;22:577-9

5)       Karabatsou K et al: Non traumatic spinal epidural hematoma associated with clopidogrel.  Zentralblatt fur Neuoshirurgie 2006;67:210-2

David S. Smith, M.D., Ph.D.

Heparin contamination -- newest findings

A series of adverse anaphylactic like reactions, mostly in dialysis patients, led to recall of Baxter Pharmaceutical brand Heparin in January, 2008.  Raw material for this heparin was sourced in China and a contaminate was suspected.  Baxter is the source for about half of the heparin used in the United States.  A supply loss of this magnitude is serious considering the ubiquity of heparin use.  Two papers from overlapping groups of investigators have used complex chemical techniques to identify the contaminate (an oversulfated chondroitin sulfate, not found in nature) and have linked this contaminate to direct activation of the kinin-kallikrein pathway in human plasma and the potential production of bradykinin, a potent vasoactive mediator.  This contaminate also generates C3a and C5a which are potent vasoactive mediators.

            Of particular interest is the speed of investigation and publication.  The first notification from the Centers for Disease Control of a potential problem was January 7, 2008.  The Heparin recall is dated January 17 and the research described above was done, the papers written, accepted and available online about 14 weeks later.  Clearly the nearly 29 investigators listed as authors, in roughly 8 laboratories made this work their first priority.

            Considering the nature of the contaminate and the fact that the authors have proposed screening techniques it is unlikely that this particular contaminate will re-occur however certain lesions can be learned.  1) The importance of reporting adverse or unexpected reactions to the FDA Medwatch web site (http://www.fda.gov/medwatch/ ).  The initial reports related to heparin came from the Missouri Department of Health to the FDA.  2) Be alert to unusual responses to medications.  The symptoms that occurred are not typical for heparin (hypotension, generalized sensations of warmth, numbness or tingling in the extremities, shortness of breath, chest tightness, and nausea.  3) Be prepared to treat the unexpected.  Though most patients recovered with cessation of the Heparin there may be as many as 103 deaths.

1)      Guerrini M et al: Oversulfated chondroitin sulfate is a contaminant in heparin associated with adverse clinical events.  Nature Biotechnology.  April 23, 2008 Advance online publication DOI 10.1038/nbt1407

2)      Kishimoto TK et al: Contaminated heparin associated with adverse clinical events and activation of the contact system.  NEJM April 23, 2008 Published on line DOI 10.1056/NEJMoa0803200

3)      MMWR: Acute allergic-type reactions among patients undergoing hemodialysis – multiple states 2007 – 2008.  MMWR Weekly 2008;57:124-125

            4)   Perrone M: FDA probes deaths from contaminated heparin.  Charleston Gazette. April 9, 2008

David S. Smith, M.D., Ph.D.