Sunday, September 9, 2007

Clinical Conundrums in Critical Care

Here is a foretaste of topical debates you can expect at the 2007 Annual ASCCA meeting in San Francisco. We invite you to express your views as comments and to prepare for lively discussion!

Posted on behalf of Dr. Avery Tung

Clinical Conundrums:
A 59 yr F with metastatic ovarian cancer undergoes pelvic exenteration under GA.

Her past medical history includes COPD, CHF, OSA, HTN on an ACEI, obesity, and NIDDM. She has previously undergone radiation and chemotherapy (Mitoxantrone). She has no allergies, and was taking Enalapril, Lasix, Metoprolol, Metformin, inhaled Beclomethasone and Albuterol 2x/day preoperatively.

She has previously had uncomplicated GA for a knee arthroscopy. Her exercise tolerance is fair…she has to rest after climbing 1 flight of stairs…but can walk 3 blocks and work in the garden without become short of breath. She can lay flat. An echocardiogram done 6 months ago reveals EF=35%, mild MR

Her preoperative vital signs were: HR 79, BP 150/90, RR 20. SpO2 on RA was 93%. BMI = 30 (86kg, 5’5”) with mild ascites on CT scan. Hct 41%, Cr 1.2, HCO3 = 32 meq/dl, K = 3.5.

The case was 8 hours long. EBL was 500cc, 800cc ascites were drained, and U/O was 170cc. Total intake included 6.5L crystalloid, 3U PRBC, 2FFP.

Abg 1 hr prior to case end was 7.32/41/128 on 100% FiO2

The patient was left intubated and brought to the ICU postoperatively. On admission, she was sedated and unresponsive. BP 108/40, HR 105. Her lines include 2 18G IVs and a R radial arterial line. Abg: 7.30/45/82 on 50% with PIP = 42 cm H20. BE = -5, Hct = 28, HCO3 = 19.

  1. Perioperative beta blockade in patients chronically on beta blockade is now a SCIP measure. This patient was on a beta blocker preoperatively. Would you restart beta blockers at this time?
  1. Would you implement lung protective ventilation in this patient (PIP <30)?
  1. This patient has no central access. Would you place a central line?

Over next 4 hours U/O (cc per hour) is low: 15, 15, 10, 5 despite Lactated Ringers infusing at 150cc/hr IV. BP 105/60, HR 95, JP draining 100/hr serosanguinous fluid, Abg 7.28/45/85 on 60%.

The urine output is low. How would you react?:

a. Continue to observe
b. Crystalloid 500cc IV fluid bolus
c. Albumin 250cc IV fluid bolus
d. More information?

You elect to seek more hemodynamic information:
Which hemodynamic monitor would you choose?

a. Echocardiogram
b. CVP
c. PA catheter

Which measure of circulatory function would you want?

a. SvO2 >65%
b. CVP >13
c. Lactate < >d. U/O >20 cc/hr

CXR now shows mild pulmonary edema. Abg now 7.26/52/60 on 60%. PIP = 36 and Hct = 26%. CVP = 14

Would you transfuse this patient?

The patient develops sepsis and ARDS. After 6 days, bowel function has not yet returned. Prealbumin = 11 and AM glucose = 196.

  1. Would you begin TPN?
  2. Would you initiate an insulin drip?

Does Epo save lives?

Efficacy and Safety of Epoetin Alfa in Critically Ill Patients
Corwin et al. NEJM Volume 357:965-976. September 6, 2007.

A multicenter study was conducted whose primary objective was to demonstrate that the administration of epoetin alfa to critically ill subjects reduces the proportion of subjects requiring red blood cell (RBC) transfusion as compared with placebo. (ClinicalTrials reference)

Secondary outcomes included:
Cumulative number of units of red blood cell transfusions received from Study Day 1 through Study Day 42.
Change in hemoglobin from Study Day 1 through Study Day 29.
Mortality through Study Day 29.
Cumulative mortality through Study Day 140.

The study was a prospective, randomized, placebo-controlled trial, which enrolled 1460 medical, surgical, or trauma patients between 48 and 96 hours after admission to the intensive care unit. Epoetin alfa (40,000 U) or placebo was administered weekly, for a maximum of 3 weeks; patients were followed for 140 days.

What did they find?

1) No difference in red cells transfused.
2) Higher hemoglobin in the epoetin alfa group.
(Hemoglobin increase = 1.6±2.0 g per deciliter vs. 1.2±1.8 g per deciliter, P<0.001)
3) A tendency towards decreased mortality in the epoetin alfa group, especially in the trauma subgroup.
(adjusted hazard ratio for death at 140 days in the trauma subgroup, 0.40; 95% CI, 0.23 to 0.69)
4) Increased thrombotic events in the epoetin alfa group.
(hazard ratio, 1.41; 95% CI, 1.06 to 1.86)

Are the findings important?

If epoetin alfa is associated with decreased mortality (independent of blood transfusion!), this is an important and new finding. The finding appeared to be most robust in the trauma patients. With any unexpected finding, it is necessary to ask whether this is merely a chance finding. Statistical significance alone is insufficient to justify a change in clinical practice. There has to be biological plausibility for a finding. The authors speculate that it may be the action of epoeitin alfa as a cytokine with antiapoptotic activity that leads to the reduction in mortality.(
JAMA. 2005;293:90-95. Kidney International (2006) 70, 246–250. Critical Care 2004, 8:337-341.) {Link to a diagram showing possible cytoprotection with epoeitin alfa}

Are there safety concerns?

Absolutely. This study found an increased risk of thrombosis in the epoeitin alfa group. Previous studies in patients with renal failure and with cancer have shown that epoeitin alfa is associated with increased risk of thrombosis and even of increased mortality. (
Lancet 2003; 362(9392): 1255-1260. J Clin Oncol 2005;23:5960-5972. J Natl Cancer Inst 2006;98:708-714. N Engl J Med 2006;355:2085-2098.)

Erythropoietin (Epo) binds its receptor (Epo R) on the surface of red blood cell progenitors in the bone marrow causing proliferation, maturation, and differentiation, thereby preventing or correcting anemia. Epo may also bind Epo R expressed on the surface of cancer cells and may elicit tumor growth via cell proliferation, protection from apoptosis, and/or angiogenesis. (See - Brower, V. (2003) Nat. Med. 9:1439.)

So what should the intensivist do?
  1. Administer epoetin alfa to all anemic critically ill patients unless it is specifically contra-indicated.
  2. Exercise clinical judgment (e.g. consider epoetin alfa in certain settings such as acute hemorrhage where patients are otherwise healthy and there is no known risk for thrombosis or cancer).
  3. Await the results of further studies.
  4. Conduct further studies yourself.
  5. Be highly skeptical and take the view that this was an industry funded study of an expensive drug that showed questionable benefit and heightened known safety concerns.
Further Reading on Erythropoietin (Review articles with free full text):

Saturday, September 8, 2007

Groundbreaking News - Insight into the Mechanisms of Action of Antibiotics

One of the major threats to global health today is antimicrobial resistance. An important finding was reported by Kohanski and others this month in the journal Cell. Researchers from Boston have discovered that there is a common mechanism of bacterial cell death induced by three different classes of bactericidal antibiotics. This common mechanism involves reactive oxygen intermediates or “oxygen free radicals.” This finding provides hope for finding new methods of combating infection. Scientists can focus on methods of amplifying the oxidative damage cellular death pathway or on inhibiting cellular repair mechanisms.

NADH oxidases located in the plasma membrane catalyze the formation of superoxide (O2-) anions. Superoxide is dismutated to hydrogen peroxide and molecular oxygen by superoxide dismutase (SOD). Catalase can convert hydrogen peroxide to water. A Fenton reaction can take place in the presence of peroxidases, leading to the formation of hydroxyl (OH-) radicals.

Here is the abstract to the intriguing article:
(From - Kohanski et al.
Cell, Vol 130, 797-810, 07 September 2007)
Antibiotic mode-of-action classification is based upon drug-target interaction and whether the resultant inhibition of cellular function is lethal to bacteria. Here we show that the three major classes of bactericidal antibiotics, regardless of drug-target interaction, stimulate the production of highly deleterious hydroxyl radicals in Gram-negative and Gram-positive bacteria, which ultimately contribute to cell death. We also show, in contrast, that bacteriostatic drugs do not produce hydroxyl radicals. We demonstrate that the mechanism of hydroxyl radical formation induced by bactericidal antibiotics is the end product of an oxidative damage cellular death pathway involving the tricarboxylic acid cycle, a transient depletion of NADH, destabilization of iron-sulfur clusters, and stimulation of the Fenton reaction. Our results suggest that all three major classes of bactericidal drugs can be potentiated by targeting bacterial systems that remediate hydroxyl radical damage, including proteins involved in triggering the DNA damage response, e.g., RecA.

Important Websites and Links

Here are some important websites. Please comment if you know of other sites that are of potential interest to critical care anesthesiologists.

Why Critical Care Medicine Is Important to the Future of Anesthesiology

Perspective of a Nonintensivist:
Why Critical Care Medicine Is Important to the Future of Our Specialty
Ronald D. Miller, M.D.
ASA April 2006 Newsletter (Extracts)
  • The creation of critical care units and evolution of critical care medicine (CCM) as a specialty were originally brought about by anesthesiologists.
  • In 2004 ASA President-Elect appointed a Task Force on the Future Paradigms of Anesthesia Practice to address the projected evolution of anesthesiologists’ clinical practices over the next 20 years.
  • Based on a broad base of information, however, the task force concluded that tertiary care hospitals of the future will be increasingly dominated by seriously ill patients who require procedures (i.e., surgical, imaging, cardiovascular) and monitored and/or critical care beds.
  • Many groups, most notably the Leapfrog Group, have strongly recommended that critical care be delivered by individuals especially trained and board-certified in CCM.
  • Major changes are occurring in many specialties, including vascular surgery, cardiac surgery and others.
  • While operating room anesthesia has dominated our specialty for many years, in planning for our future, we would be well served to diversify our value to medicine specifically and society overall.
  • Encouraging additional training in CCM and also encouraging anesthesiology residents to take critical care fellowships would provide a sound basis for our specialty’s role in the future tertiary care hospital.
  • Significant involvement with CCM is crucial for our specialty’s future and the welfare of CCM overall.
  • The combined training of anesthesiology and CCM creates the knowledge and skills for the physician leaders of the future tertiary care hospital and potentially with different models of care, the leaders for inpatient care generally.
  • The methods to accomplish this goal include incorporating more critical care experience in our residency programs, lengthening our residencies, encouraging incentive-based choices of our fellowships or even redesigning some of our residencies to provide a combined anesthesiology and CCM residency for board certification in both specialties.
Ronald D. Miller, M.D., is Professor and Chair, Department of Anesthesia and Perioperative Care, University of California-San Francisco, San Francisco, California.

Friday, September 7, 2007

The Aims of this Weblog

Welcome to the Critical Care Anesthesiologists' Weblog!
The aims of this Blog include:

  1. To promote the specialty of Critical Care Anesthesiology in the US (and elsewhere).
  2. To garner support for the ASA and the ASCCA.
  3. To provide a forum for anesthesiology residents and anesthesiology intensivists.
  4. To address controversies in critical care.
  5. To stimulate academic curiosity and debate.
  6. To provide news of events, meetings and courses relevant to critical care anesthesiologists.
  7. To draw attention to groundbreaking news and research in critical care.
  8. To direct people to relevant resources, such as websites, academic departments and journals.
  9. To educate through quizzes, clinical cases and medical mysteries.

We look forward to your comments and contributions.
ICU Bloggers.