Long term consequences
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Long Term Consequences. Anesthetic Choice/Management. Goals. Perioperative management implications for cancer patients. PeriOperative Morbidity & Mortality. 1980’s Anesth mortality was 1:10,000 now this is closer to 1:100,000 Δ Mandated SpO2, ETCO2, NIBP,ECG and AAM technology

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Anesthetic Choice/Management

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Long term consequences

Long Term Consequences

Anesthetic Choice/Management



Perioperative management implications for cancer patients

Perioperative morbidity mortality

PeriOperative Morbidity & Mortality

  • 1980’s Anesth mortality was 1:10,000 now this is closer to 1:100,000

  • Δ Mandated SpO2, ETCO2, NIBP,ECG and AAM technology

  • 10% all cause mortality (age 65+) in the year after surgery is 10,000 X more common than preventable anesthetic deaths but ......

  • Increasing evidence suggests PeriOp management may have long term consequences – PO Neuro Cognitive , Surg Site Infection and Cancer Recurrance

Recent anesthetic management history

“Recent” Anesthetic Management History

  • 90’s periOp B blockers reduce all cause mortality @ 1 year ( Swedish study with Atenolol)

  • NA studies had more aggressive end pts and there was a significant increase in PeriOp strokes

  • Spinals/epidurals (pelvic,urologic,major ortho) blood loss , DVTs, chronic incisional pain and PONCD

More history

More History

  • Terri Monk – BIS monitor observational study reported a 3 fold increase in one year mortality in elderly patients with deep anesthesia. This has now spawned the “B Aware” trials. She also noted;

  • More pronounced effects of anesthetic agents in patients with carcinoma and commented on;

  • Significant adverse long term consequence to GA esp at the extremes of age

  • Learning & behavioural issues ≤ 2 years (possibly age three in most recent studies)

  • Neurocognitive decline - elderly

One of monk s conclusions

One of Monk’s conclusions

  • “We must investigate the mechanisms by which patients with cancer respond to standard anesthetic doses with more pronounced cortical electrical depression and how pharmacokinectics and dynamics are altered in pre existing disease states”

Pharmacologic implications for another time

Pharmacologic Implications – foranother time

  • IARS Smart Tots® research initiatives on pediatric inhalational anesthesia - (neuroplasicity, agent toxicity vs stress) i.e. This is more than separation anxiety!

  • Ketamine ( nmda receptor inhibitors)

  • Illicit substances ( Ecstasy, Amphetamines, Cocaine, crystal meth ......)

  • Etomidate

Are anesth surg during infancy associated with altered academic performance during childhood

Are Anesth & Surg during infancy associated with altered academic performance during childhood?*

Ca surgery generalizations from the lab

Ca Surgery : Generalizations from the lab

  • Surgical manipulation – tumor cell release into lymphatics and blood stream

  • Micro metastases already present prior to surgery

  • This MINIMAL RESIDUAL DISEASE can result in clinical mets when there is a balance shift between the patient’s immune status and the tumors’ ability to seed,proliferate and attract new blood vessels

Periop balance shift surgery per se

PeriOp balance shift * Surgery per se

  • Tumor cells released into circulation

  • cell mediated immunity ( T cell and NK cell function)

  • Increased Vascular Endothelial and other growth factors ( Normally promote wound healing but are pre empted by malignant cells)

Periop balance shift volatile inhalational anesthetics

PeriOp balance Shift* Volatile inhalational anesthetics

  • Dose/patient specific dependent depression of neutrophil, macrophage, dendritic cell, T cell and NK cell immune functions

Periop balance shift opiods

PeriOp Balance Shift* Opiods

  • Morphine, and to a lesser degree synthetic narcotics, decrease cellular and humoral immune function. Systemic administration has been associated with a proangiogenic action promoting tumor growth.

  • By contrast most non opiod analgesia preserves NK cell function and, in rodents, reduces metastatic tumor spread.

Mor opiod receptor

MOR –  Opiod Receptor

  • Red – single nucleotide polymorphisms

Neoplastic variability

Neoplastic Variability

  • MOR – u opiod receptor

  • VEGF – vasc endo growth factor

  • Various mammallian tumor cell lines result in enhanced specificity of the mediators of angiogenisis

Anesthetic choice management

 Opiod Receptor Gene A118G polymorphism predicts survival in patients with breast cancerBortstov AV et al Anesthesiology April 2012 896-902

  • Genotype stratification was correlated to breast cancer specific mortality

  • One further observation re European American vs Afro American breast cancer survival data

Regional anesthesia spinals epidurals

Regional Anesthesia;Spinals & Epidurals

  • Prevent Neuroendocrine Stress by;

  • Blocking afferent neural traffic

  • Blocking descending efferent activation of the sympathetic nervous system

    Note: narcotic doses required to generate a stress free surgical anesthetic are impractical in most instances.

Regional general combo

? Regional – General Combo

  • If pre incision functioning block then  Neuroendocrine stress

  •  volatile anesthetic requirements

  •  post op opiods

  •  endogenous opiods (endorphins)

    Caveat: adequate perfusion pressure

Random but associated studies

“Random”, but associated studies

  • Paravertable blocks; 4 fold  in recurrence or mets in breast Ca

  • Primary melanoma excision; if GA vs local or regional anesthesia: -ve predictive value 1.46 for survival

  • Epidural anesthesia for Radical Prostatectomy, colonic cancer surgery and Ovarian Serous Adenocarcinoma – variable but  survival or “cancer free” period

Other periop decisions

Other PeriOp decisions

  • Blood transfusion

  • Glucose control

  • Fluid management

  • Inhalational anesthetic toxicity – newborns

  • Persistent incisional pain

  • Beta blockers

  • central ᾄ agonists – clonidine


  • NMDA receptor blockers

Anesthetic choice management

Long term survival after colon cancer surgery:A variation associated with the choice of anesthesiaChristopherson R et al AnesthAnalg 2008:107;325-32

  • A subset of the CSP #345 ; the effect of Epidural Anesthesia/analgesia on perioperative outcome

  • Prospective, randomized

  • Aortic,gastric,biliary and colonic surgery Mar 92 to August 94 – followup to Dec 2002

  • Epidural .5% bupivacaine, Epi 1:200,000 : T6 block prior to GA

  • End pts; ,MI,CHF,HB,BP,PE,Resp failure,cerebral insults,ARF : were all NS at 30 days

  • Post op pain, ambulation, LOS

345 n 1021 colonic ca sub group

#345 (n=1021) Colonic Ca sub group

  • 247 pts with complete followup of 177

  • also of note: 70 not in study had similar survival experience

  • 92 GA, 85 EGA

  • IV post op opiods or 48+ hours epidural analgesia

  • GA: Isoforane, N2O,Vecuronium,fentanyl

Anesthetic choice management

Long term survival Colonic CaChristopherson R et al AnesthAnalg 2008Median survival: mets 2 yrs, no mets 6.1 yrs

Long term survival colonic ca christopherson r et al anesth analg 2008

Long Term Survival colonic CaChristopherson R et al AnesthAnalg 2008

Anesthetic choice management

Epidural vs Traditional Pain Mgmt – Survival & Ca recurrance after Colectomy . Cummings KC etalAnesthesiology April 2012: 797- 805

  • N=42151 with 23% epidural during resection

  • 1996-2005, > 65 years with 4 year follow up minimum

  • > 1 year increase all cause survival in epidural group

  • No change in cancer reccurance rate

Anesthetic choice management

Anesthetic Technique for Radical Prostatectomy Surgery Affects Cancer Recurrance – Retrospective Analysis Biki B et al Anesthesiology 2008: 109; 180-7

  • Patients for RP Jan 94- Dec 03 f/u to Oct 06

  • GA; fentanyl 1-2 ug/kg, propofol 1-2mg/kg,.5mg/kg atracurium N2O/O2, Diclofenac 75-100 bid

  • T11-12 epidural Rx prior to surgery vs post op IV PCA

  • If Epidural patients required post op IV morphine they were included in the GA group n=6

Anesthetic choice management

Anesthetic Technique for Radical Prostatectomy Surgery Affects Cancer Recurrance – Retrospective Analysis Biki B et al Anesthesiology 2008: 109; 180-7 ......cont

  • GA/PCA =123, Epidural/GA =102 : #s in each group determined by preferences, relative contraindications etc

  •  was NS but ASA score,complications & surg time in epidural group

  • Primary outcome “biochemical recurrence” ie

     PSA from post op nadir  possible Rad Rx, endocrine or chemo Rx

Radical prostate lymph node dissection

Radical Prostate, lymph node dissection

Anesthetic choice management

Potential Influence of the Anesthetic Technique used during Open Radical Prostatectomy on Prostate Cancer related Outcome Wuethrich PY et al Anesth 2010:113;570-6

  • retrospective study

  • Jan94-June97 n=103 GA+TEA, 45 not incl re inadequate TEA

  • July97-Dec2000 n=158 GA+ Morphine/Ketoloric

  • Primary Outcomes

  • Biochemical recurrence free survival

  • Clinical progression free survival

  • Cancer specific survival

  • Over all survival

Potential influence rad prostate wuethrich et al anesthiology 2010

Potential Influence Rad ProstateWuethrich et al Anesthiology 2010

  • Standardized GA incl fentanyl 2 ug/kg, N2O,forane

  • T10-12 TEA .25% bupivacaine 8-10 cc/hr, No COX inhib

  • PostOp .1% bupivacaine/fentanyl 2ug/cc @ 8-15 cc/hr X 48 hrs

  • Limitations TEA group – higher ASA, 2X infusion rate and less fentanyl (confounding variables)

Potential influence rad prostate wuethrich et al anesthiology 20101

Potential Influence Rad ProstateWuethrich et al Anesthiology 2010

Potential influence rad prostate wuethrich et al anesthiology 2010 disscussion

Potential Influence Rad ProstateWuethrich et al Anesthiology 2010 Disscussion

  • Excess prostaglandin release and endogenous cortisol  immunosuppression

  • NSAIDS inhibit prostaglandin synthesis

  • Cyclooxyngenase 2 is induced in “tumor promoters” – prostaglandin synthesis increase prostate cell lines while COX2 inhibitors induce apoptosis (cell death)

Anesthetic choice management

Do Intraoperative Analgesics Influence Breast Cancer Recurrence after Mastectomy? A retrospective analysisAnesthAnalg 2010: 110; 1630-5

  • 327 mastectomy/Axillary dissection chart reviews – 1 surgeon, 1 Oncologist, 2 anesthetists ( Feb ‘03- Sept ‘08)

  • 8 excluded re pulm mets, incomplete op etc.

  • Pre incision: Clonidine or Ketamine or Ketoloric, all received postOp diclofenac & acetaminophen

  • GA sufentanil, STP or propofol, Sevo or Des plus Air/Oxygen

Breast ca recurrance ketalorac

Breast Ca recurrance / Ketalorac

Anesthetic choice management

The Effects of Anesthetic Technique on Cancer Recurence ---RFA Small Hepatocellular CarcinomaLai A et all A&A 2012; 114: 290-6

  • Retrospective review Aug 1999 – Dec 2009 ; 179 consecutive pts with < 3cm hepatic tumors

  • End points - overall and recurrence free survival

  • Epidural (T8-10 1.5% lidocaine) vs GA (Fentanyl, Propofol TIVA)

  • Study limitation – adequate epidural anesthesia was not defined

  • Study results ???

Anesthetic choice management


Rfa hepatocellular ca hazard ratios

RFA Hepatocellular Ca ......Hazard ratios:

  • Recurrance free survival; Epivs GA (3.66), Tumor # (2.28), GGT ( 1.39)

  • Overall survival; Liver function (2.30), Tumor # (2.36) GA no benefit in overall survival

  • Inverse probability weighted Epivs GA = 1.26

    Epidural anesthesia for this procedure can be associated with referred pain requiring add’nopiods. This could also limit current intensity or duration of therapy. Epi patients did not have any opiod sparing in the post op period.

Spa vs ga for lower limb mm br j anaesth june 15 2012

SpAvs GA for lower limb MMBR J Anaesth June 15 2012

  • Mortality during a 10 yr Obs study

  • 52 SpA vs 221 GA

  • Trend toward better Cumulative survival rates in patients who received spinal anesthesia:

  • SpA 96 months (CI 81-111)

  • GA 69 months (CI 50-88)



What do we know about surgical stress response and Cancer?

A mine field periop period

A mine field – Periop period

  • Opiods – analogs of morphine – u3

  • Cox inhibiters

  • Alpha adrenergic antagonists

  • Beta blockers

  • Inhalational anesthetics

  • Regional anesthesia

  • TRIM ( transfusion related immunomodulation)

  • Hypothermia

  • Sepsis

  • Statins

  • Etomidate

Are ga s always bad for ca recurrance

Are GA’s always bad for Ca recurrance?

The answer is : IT DEPENDENDS

Anesthetic choice management

Volatile Anesthetics Reduce Invasion of Colorectal Cancer cells thru down regulation of matrix metalloproteinase -9Muller Edenborn et al Anesthesiology 2012 117: 293-301

  • Malignant tumors invade extracellular matrix

  • Surgical clamping triggers a reperfusion injury by upregulation of MMP9 (neutrophils,a rich source of MMP9, accumulate because of IL 8)

  • Complex in vitro study demonstrated volatile anesthetics reduce reperfusion injury – this is not new

  • But indices of colorectal matrix invasion were reduced



Data suggests;the possibility that anesthetic conduct may contribute to the recurrence of cancer ( liberal opiod Rx or inadequate analgesia)

Equally worrying is the possibility that anesthesia, or the stress response to surgery could activate dormant cancer cells in an individual undergoing non cancer surgery.

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