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

Lots of pain in the United States

Krueger and Stone used a telephonic random digit dialing technique in an attempt to contact 10700 people to seek their participation in a survey about the occurrence and severity of pain across randomly sampled 15 minute intervals of the day. Their final sample was 3982 people (a 37% response rate).  They used a 7 choice rating scale for pain intensity and found that 28% of men and 26% of women reported feeling some pain at the sampled times.  Those with lower income or less education spent a higher proportion of their time in pain and reported a higher proportion of time in pain than did those with higher income and more education.  The authors note the high cost of pain with respect to medication and lost time from work.  They estimate that the combined cost of outpatient prescription analgesics and lost productivity was nearly 75 billion dollars.  Krueger AB and Stone AA: Assessment of pain: a community-based diary survey in the USA.  Lancet 2008;371:1519 - 1525

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

Edema after lung resection? Try aerosolized salbutamol

Patients after lung resection have a 2-5% incidence of acute lung edema even when precautions such as low tidal volumes, PEEP, recruitment maneuvers and fluid restriction are used.  The authors built on existing information about the role of epithelial B-adrenergic receptors in the regulation of active sodium transport mediated clearance of excess intra-alveolar fluids and prior studies showing that B-adrenergic agonists attenuate lung vascular injury and accelerate the resolution of alveolar edema to design a cross-over study to examine the effects of a B-adrenergic agonist (salbutamol) on lung water after lung resection.  They enrolled 21 patients they determined to be at high risk for postoperative lung edema.  All patients had thoracic epidural anesthesia, double lumen tubes and were extubated at the completion of surgery.   Post operatively the patients were administered either 5 mg of nebulized salbutamol or ipratropium (an anticholinergic bronchodilator) in a cross over design with a 6 hour washout period between drugs.  Preoperatively this high risk group had a mildly elevated extravascular lung water index (EVLWI) of 7 – 8 ml/kg.  Post-operatively, but before the study drug, the EVLWI was increased above the preoperative value to 10 and the ratio of PaO2/FiO2 was decreased.  On post operative day 0, salbutamol nebulization induced a reduction of EVLWI and increased the PaO2/FiO2 ratio.  In contrast nebulized ipratropium produced no changes in these variables.  Salbutamol also increased cardiac contractility and cardiac index.  Thus nebulized salbutamol reduced pulmonary water content, enhanced cardiac performance and improved oxygenation in this group of patients.  The study was too small to determine the impact of treatment on outcome.  Lecker M et al: Aerosolized salbutamol accelerates the resolution of pulmonary edema after lung resection.  Chest 2008;133:845-852.  There is an accompanying editorial on page 833 of the same issue.

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

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.

The incidence of spinal cord injury after epidural catheters

           The exact incidence of neurologic dysfunction from hemorrhage after neuraxial blockade is not known.  Horlocker sites the ASA closed claims data base noting that during the 1990s spinal cord injuries were the leading cause of claims and spinal hematoma accounted for half of these injuries.  In many cases, the diagnosis was delayed as the most typical presenting symptoms, numbness or weakness, were often attributed to the effect of the local anesthetic.  Horlocker also cited a study in Sweden of serious neurologic complications among 1,260,000 spinal and 450,000 epidural blocks performed over a ten year period.  They found 33 spinal hematomas.  A coagulopathy was present in 11 of these patients.  In this series an elderly woman undergoing knee arthroplasty had a 1 in 3,600 risk of epidural hematoma and a woman undergoing hip fracture surgery under spinal anesthesia had a risk of spinal hematoma of 1 in 22,000 compared to a risk of 1 in 480,000 to all patients undergoing spinal anesthesia.  This study noted risk factors for spinal hematoma to be age, associated abnormalities of the spinal cord or vertebral column, presence of an underlying coagulopathy, difficulty during needle placement, and an indwelling neuraxial catheter particularly when combined with standard heparin or LMWH anticoagulation.

            Horlocker recounted the experience with LMWH in the United States.  The drug was introduced in 1993.  Within the first year there were two reported cases of spinal hematoma.  Thirty cases were reported between 1993 and 1997.  At the time of the first ASRA consensus conference there were 45 reported cases and 40 involved neuraxial anesthesia.  Less then one third of the patients reported fair or good neurologic recovery.  Delayed diagnosis appeared to be a recurrent problem.

            Horlocker also warns of off label used for LMWH.  Increasingly it is being used as a “bridge” therapy for patients (including parturients) chronically anticoagulated with coumadin for various reasons.  The doses used for this purpose are considerably higher than those used for DVT prophylaxis.

            Horlocker TT: Analgesia without paraplegia: Neuraxial anesthesia and anticoagulation.  Conferencia Magistralas 2006;29:S35-43 – If you want a single article to read on these issues, this is one of the better ones (DSS)

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.

Avoiding epidural hematoma related paralysis

The increasing use of platelet inhibitors (clopidogrel, Plavix) because of drug eluting stents makes careful drug history taking even more important then previously to avoid placing epidural catheters or performing subdural punctures on patients who might not clot quickly if a vessel is entered.  As prevention of deep vein thrombosis is now a national patient safety goal and as fewer insurance companies compensate for the costs associated with treating post operative blood clots, expect more aggressive post operative DVT prophylactic therapy including the use of low molecular weight heparin (Lovenox).  Thus prior to discussing post operative epidural analgesia with a patient it is necessary to know the post operative DVT prophylaxis planned by the surgical service.  In general these guidelines follow the ASRA guidelines regarding conduct of regional anesthesia in the anticoagulated patients (Reg Anesth Pain Med 2003;28:172-197). The following is the position of the UPENN Anesthesia Pain Service with respect to these issues: 

            Patients receiving anticoagulants for DVT prophylaxis or antiplatelet drugs post cardiac stenting are at a small, but real, risk of epidural hematoma if epidural catheters are placed or removed.  This includes the use of low molecular weight heparin (LMWH), unfractionated heparin or antiplatelet drugs such as clopidogrel (Plavix), NSAIDs or aspirin.  In addition it appears that the risk of harm increases with dose and with duration of therapy or when more than 1 anticoagulant is used.  Consequently:

1)      Patients who are taking LMWH or clopidogrel are not candidates for post operative epidural analgesia.  There is some data to suggest that the use of low-dose once a day LMWH is safe to use in patients with an epidural.  However the dosing used in the United States is commonly moderate to high dose, or twice a day dosing, both of which are contraindications to epidural use.

2)      Patients taking clopidogrel for whom an epidural catheter is desired should be taken off the drug for 7 days prior to the planned epidural catheter placement.

3)      Patients taking LMWH for whom an epidural catheter is desired should be taken off the drug for 12 hours if on once a day dosing or 24 hours if on twice a day dosing before epidural catheter insertion.

4)   Patients in whom an epidural catheter has been placed should not be started on LMWH or clopidogrel until the epidural catheter is removed.

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.

An engineer's personal encounter with an OR fire

Fourteen year's ago Dennis Parker lost his son as a consequence of an OR airway fire.  His first person account was recently published in AORN connections and is reproduced here.

Download an_engineers_commitment_to_safety_in_the_or_pp_1_89.pdf

Reprinted with permission from AORN connections (September 2007) newsletter. Copyright 2007 AORN, Inc., 2170 S Parker Rd, Suite 300, Denver, CO 80231.  All rights reserved

Who is my doctor?

“It is unfortunately common for a patient to be caught up in a parade of tests, treatments and subspecialists with no physician clearly responsible for the whole problem.  Patients find themselves required to be their own physicians, making lonely decisions about high technology matters that doctors have trouble figuring out.  On occasion the patient is cared for by a “team” and cannot figure out the politics of responsibility and leadership – with the result that despite so many caregivers, the patient may be essentially alone at critical junctures.” From Chapter 5, The mysterious relationship between doctor and patient. In Cassell EJ: The Nature of Suffering and the Goals of Medicine (2^nd edition), Oxford University Press, 2004 page 65

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

Intraoperative awareness - potential causes and decreasing the risk

AIMS is a large, anonymous, multicenter, reporting system of anesthesia incidents that is in widespread use in Australia and parts of Asia.  Bergman et al examined the data base when there were 8372 abstracted reports collected between 1988 and 2001.  The authors queried on the keyword “awareness.”  Using specific definitions of awareness they found 81 reports of which there were 50 cases of definite awareness and 31 with a high probability of awareness.  They could find no obvious cause for awareness in 13 (16%) of the cases. Low inspired volatile agent concentration appeared to be responsible for 36 (44%) of the 81 cases.  In 14 of these cases there was no agent monitor present.  Five of these cases appeared to be due to prolonged attempts at intubation and four cases were due to reducing delivered anesthetic secondary to hypotension or cardiovascular instability.  Thirty two cases were due to inadvertent paralysis of an awake patient.  Case review suggested that inattention or distraction were contributory in 20 cases, haste in 14 and fatigue in 5.

            This study covers a later period than did the closed claims analysis study of awareness (Domino KM et al: Anesthesiology 1999;90:053-61).  In my opinion, at least in the United States, the 1988 – 2001 period is reasonably similar to current practice yet awake paralysis persists and in Bergman et al awake paralysis was the most common cause for awareness.  Picking up the wrong syringe (a paralytic instead of the desired drug) was a recurrent cause of awareness.  Keeping syringes of paralytic drugs away from other drugs might help reduce this problem.  The authors expressed particular concern about the incidents of awareness with no apparent cause.   Two of the 13 cases had agent analyzers and apparently adequate doses of volatile agent.  Two cases occurred during ECT when no volatile agent is typically used.

            Neither this study nor the closed claims study allows calculation of incidence since the total number of cases from which these reports are drawn is not known.  In addition reporting is voluntary and the threshold for reporting most likely varied from practitioner to practitioner.  Finally if patient report was the major source of information then there was most likely underreporting as most patients do not volunteer awareness information unless repeatedly asked.  However, despite these weaknesses, this paper provides an intensive study of a serious of events providing conclusions as to cause and approaches for decreasing the risk of the occurrence of awareness.

            The authors presented eight suggestions based on their data that they feel will help reduce awareness (table 4 modified):  1) Check the anesthesia machine before each use; ensure a correctly mounted and filled vaporizer. 2) When using a volatile agent use an end-tidal agent monitor.  Use a low level alarm set for a sufficient volatile agent concentration to prevent awareness. 3)  Provide further hypnotic doses for repeated intubation attempts. 4) Be aware of the potential for awareness in hypovolemic patients receiving low concentrations of anesthetic.  Restore appropriate anesthetic concentration as soon as possible. 5) Routinely use a peripheral nerve stimulator and ensure sufficient anesthetic concentration until muscle power returns. 6) When using total intravenous anesthetics, ensure a patent intravenous line and periodically check the infusion pump to confirm drug administration. 7) Clearly label all drug syringes immediately when they are drawn up.  Check this label carefully before administration.  Do not rely on recognition of syringe size to confirm its contents.  Consider newer methods of ensuring that the correct drug is given. 8) Consider a depth of anesthesia monitor, if not routinely then for selected cases.

Bergman IJ et al: Awareness during general anesthesia: a review of 81 cases from the Anesthetic incident monitoring study (AIMS).  Anaesthesia 2002;57:549-556

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

Race and socio – economic status influence acceptance of post operative epidural analgesia

Ochroch and associates (Anesth Analg 2007;105:1787) used a survey of patients scheduled for elective surgery to determine rates of acceptance of post operative epidural analgesia.  Over a four month period a trained research technician contacted the patients the day prior to their scheduled admission and then conducted a standard survey by telephone.  3739 patients were called at home, 1265 were contacted and 1193 consented to participate in the study.  64% of the study participants said that they would accept an epidural if recommended by an anesthesiologist and 36% said they would refuse.  The rate of acceptance increased to 78% if the epidural was recommended by both the surgeon and anesthesiologist with 22.5% still refusing.  A univariate logistic regression showed that patients with higher incomes, more education and who where employed full or part time were more likely to accept an epidural.  African Americans were far less likely then Caucasians to accept an epidural.  When controlling for gender, education level, employment type income and marital status, African American race predicted refusal of epidural analgesia. (OR 0.58, 95 % 0.32 – 0.78)  The authors attempted to determine some of the reasons for refusal but were unable to do so.  Of concern then is a group of patients who for some reason absent themselves from a proven form a post operative pain therapy that may have benefits with respect to reduced pain and improved recovery.  Of interest, from my observations, is the high acceptance of epidural analgesia on the HUP labor floor in a patient population that has a large number of African Americans (DSS comment).

Edward Andrew Ochroch M.D., MSCE is Associate Professor of Anesthesiology and Critical Care at the Hospital of the University of Pennsylvania

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

A proposed mechanism for isoflurane induced apoptosis

Wei and associates continue their investigations into isoflurane toxicity in this paper from Anesthesiology (2008;108:251 – 260).  Using a variety of cultured cell types they showed that isoflurane activates the endoplasmic reticulum membrane inositol 1,4,5-triphosphate (IP3) receptor.  This activation produces excessive calcium first in the cytosol and then in mitochondria.  It is this higher calcium level that triggers apoptosis.  There was considerable variability in the sensitivity of the various cell lines to isoflurane induced apoptosis.  The authors note that certain cases of familial Alzheimer’s or Huntington disease have enhanced IP3 receptor activity and thus may be more sensitive to the toxic effects of isoflurane.  Recognize the difficulty of extrapolating from cell cultures, to organs or whole animals.  Thus, it is my belief, that further work is necessary before clinical practice is altered by findings such as these (DSS comment).

Huafeng Wei, M.D., Ph.D. is Assistant Professor of Anesthesiology and Critical Care at the University of Pennsylvania

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

Risk for thromboembolism in hospitalized patients is high; the rate of appropriate prophylaxis is far too low

A recent paper and an editorial in the Lancet discussed the high rate of complications from venous thromboembolism (VTE) in both surgical and medical hospitalized patients and the relatively low rate of VTE prophylaxis.  They note that pharmacological prophylaxis reduces the risk of pulmonary embolism in general surgical patients by 75% and by 57% in medical patients.  However a cross sectional survey of nearly 70,000 hospitalized patients in 32 countries revealed that though 66% of surgical patients and 40% of medical patients were eligible for VTE prophylaxis only 59% and 40% of the at risk patients received this potentially lifesaving therapy.  Data from United States Centers appeared better than the overall.  Of the at risk surgical patients 80% were receiving some sort of prophylaxis and 71% were receiving the American College of Chest Physicians recommended prophylaxis.  However only 64% of at risk medical patients were receiving any sort of prophylaxis.  From 1) Cohen AT et al: Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study); a multinational cross-sectional study.  Lancet 2008;371:381- 394 2) Ageno W, Dentali F: Prevention of in-hospital VTE: why can’t we do better? Lancet 2008;371:361-362

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

Coagulopathy and tranfusion

A low ratio of fresh frozen plasma to RBCs decreases mortality in patients receiving massive transfusions at a combat support hospital (Borgmann MA et al, J Trauma 2007;63:805 – 813).  The authors performed a retrospective review of the records from 246 soldiers with combat injuries who received massive transfusions (> 10 units of RBC in 24 h).  In the paper’s introduction the authors note that about 5% of patients admitted to Iraq US combat support hospitals require massive transfusion.  They note that mortality rates among these patients is more than 30% and that a considerable portion of this mortality appears related to the lethal triad of hypothermia, metabolic acidosis and coagulopathy.  Penetrating injuries were present in 94% of the group, 1% of the injured were female, and the median age was 24.  The median injury severity score (ISS) was 18 and the overall mortality was 28%.  The authors used a statistical process to divide the group into low, medium and high plasma to RBC groups with the low group having a plasma to RBC ratio of 1:8, the medium having a ratio of 1:2.5 and high with a ratio of 1:1.4.  Mortality decreased as the ratio of fresh frozen plasma to RBCs increased with a mortality of 65% in the low, 34% in the medium and 19% in the high group.  With respect to primary cause of death, hemorrhage related death was less in the high ratio group (37%) compared to the low ratio group (92.5%) producing a relative reduction of 60%.  The authors concluded that for patients with significant traumatic injuries requiring massive transfusion survival improved when fresh frozen plasma and RBCs are administered in near equal volumes (a ratio of 1:1.4).  The authors noted that those patients who received large amounts of fresh frozen plasma early required less total fluid in the first 24 hours.  They also noted that those in the low or medium plasma to RBC ratio groups often died of hemorrhage with a median time of death of 2 to 4 hours.  Remember however that this is a retrospective study with the high, medium and low ratio group created after the fact.

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

Reversing lung collapse and hypoxemia in early ARDS

Barry Fuchs (Medical Director of MICU, HUP, UPENN) calls our attention to a recent paper on the use of the recruitment maneuver to reverse lung collapse.  The new information in this paper relates to the degree and duration of the recruitment maneuver.  From the abstract: Objectives: To test if a bedside recruitment strategy, capable of reversing hypoxemia and collapse in 95% of lung units, is clinically applicable in early acute respiratory distress syndrome.  Measurements and Main Results: Twenty-six patients received sequential increments in inspiratory airway pressures (5 cm water steps) until the sum of PaO2 + PaCO2 was greater than or equal to 400 mm Hg or preset stopping criteria of mixed venous saturation less than 80%, mean arterial pressure less than 60 mmHg or barotrauma identified by CT was met.  Whenever the primary target was not met, despite inspiratory pressures reaching 60 cm H2O, the maneuver was considered incomplete. Late assessment of recruitment efficacy was performed by computed tomography (9 patients) or by online continuous monitoring in the intensive care unit (15 patients) for up to 6 h. It was possible to open the lung and to keep the lung open in the majority (24/26) of patients, at the expense of transient hemodynamic effects and hypercapnia but without major clinical consequences.  No barotrauma directly associated with the maneuver was detected. There was a strong and inverse relationship between arterial oxygenation and percentage of collapsed lung mass (R 0.91; p < 0.0001).  From Borges JB et al: Am J Respir Critic Care Med 2006;174:268.

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

Anesthesiologists and nurses apparantly infect patients with hepatitis C because of unsafe practices that have been previously demonstrated to transmit disease

It can be difficult to discern the exact nature of events from the initial news stories however it appears that physicians and nurses in an outpatient endoscopy clinic located in Las Vegas Nevada improperly drew doses of sedatives for patients from a single multi dose vial possibly exposing 40,000 patients to a risk of hepatitis C or aids.  Apparently they did not use a fresh syringe and needle for each entry into the vial so that transmission between patients via the vial contents was possible.  I cannot believe this has happened – it seems so contrary to every teaching on disease transmission and current safe practice.  Do not even consider reusing the same syringes or needles between patients.  Any item that is used on more than one patient should be designed for such use and properly disinfected between uses.

However the above is not a unique event.  On several occasions in the recent past anesthesiologists have been identified with transmitting Hepatitis C through the misguided practice of syringe/needle reuse and multi dose vials.  In 2002 there was a hepatitis C outbreak in Norman Oklahoma related to needle and syringe reuse.  About 71 people were infected there.  In 2007, an anesthesiologist from Dix Hills New York was associated with a cluster of Hepatitis C infections related to his practice.  As a result 11,000 of his former patients were contacted about infection risk.  Also in 2007 another anesthesiologist, was sued for Hepatitis C transmission from faulty infection control practice while giving anesthesia for colonoscopy.  This last anesthesiologist practiced at about 10 different physician offices and about 4,500 of his former patients were placed at risk because of his failure to use reasonable infection control.

The ASA newsletter (66:2002) provides a summary of the ASA infection control guidelines: 1) Syringes and needles are sterile, single-patient-use items. 2) After entry into or connection with a patient’s intravenous infusion, the syringe and needle should be considered contaminated and used only for that patient. 3) Medication from a syringe must not be administered to multiple patients even if the needle on the syringe is changed. 4) All infusion fluids, administration sets (intravenous tubing and connections) and pressure transducer setups are single-patient-use items. Absence of blood contamination cannot be guaranteed by visual inspection. 5) Sterile needles and syringes should always be used to aspirate the contents of an ampule or vial. 6) Each time a multidose vial is entered, aseptic techniques should be used, including cleansing the rubber stopper with alcohol and using a sterile needle and syringe. If visible contamination of a multidose vial has occurred or if sterility is questionable, the vial should be discarded. 7) Immediately after use, or at least at the end of each patient’s anesthetic, all used syringes and needles should be discarded in an appropriate puncture-resistant sharps container. Unused syringes, needles and related items should be stored in a clean area to avoid contamination by contaminated syringes and equipment. 8) Health care workers with breaks in the skin or exudative or weeping lesions should refrain from direct patient contact and from handling patient care equipment unless the open area can be protected. Strict attention to hand washing, hand antisepsis, aseptic technique and use of gloves and other barrier precautions is important to avoid transmission of pathogenic microorganisms to patients and health care workers.

There apparently persists the misguided concept that injecting high on the iv tubing is safe.  This is wrong!  The ASA Newsletter article cited above notes the following: In 1990, Trepanier et al. investigated the risk of cross-infection related to the multiple use of disposable syringes for anesthesia in the operating room. The rate of blood contamination in the intravenous (I.V.) tubing was 3.3 percent at the injection site closest to the I.V. catheter and 0.3 percent at the furthest site. The presence of a one-way check-valve did not affect the contamination rate. Trepanier and his group also found that changing the needle alone on a used syringe was useless for preventing contamination of blood into the syringe.

Considering the difficulty in maintaining sterility and preventing contamination of multi dose containers several states are considering a ban on their use for most medications.  Once a syringe is connected to a patient’s IV it is by definition contaminated and should never be used on another patient.  If a multidose vial has been entered by a syringe and needle that has been in contact with a patient that vial is also contaminated and should be discarded once the care of that patient is over.  It would be prudent not to use multidose vials between patients but to discard the remaining drug at the end of each case.  A