ANESTHESIA CONSIDERATIONS FOR

SIMULTANEOUS PANCREAS-KIDNEY TRANSPLANTATION

AND POST-REPERFUSION

SYNDROME: A CASE REPORT AND REVIEW OF

THE LITERATURE Christopher J. Patton, BSN

Barnes-Jewish College

CASE STUDY

REPEAT SPKT

• 43-year-old, ASA 3, 47 kg female• Underwent primary SPKT two years

earlier– Pancreatic graft failure due to severe

pancreatitis – Renal graft failure secondary to rejection

• History: IDDM, ESRD, Anemia, GERD, HTN, HLD

• Anesthesia History: Unremarkable• Allergy: Cephalexin (rash)

PREOPERATIVE ASSESSMENT

• Airway: Mallampati III, TM distance = 5 cm, normal cervical extension

• Hypertensive: MAP 100 - 125 mm Hg • ECG: NSR with poor R-wave progression • Negative nuclear stress test• TTE: Normal EF, mild LVH/LAE, trace

MR/TR • CXR: Remarkable only for an in situ left

subclavian HD catheter with its tip at the atriocaval junction

PREOPERATIVE ASSESSMENT

• Lungs CTA bilaterally• Normal heart tones• No carotid bruits• Labs: – Elevated Cr and PO4 (4.43/6.0 mg/dL,

respectively)–Decreased H & H (9.9/28.8 g/dL)

• Severe N/V: three episodes of emesis in the holding area – Treated with transdermal scopolamine, two

doses of odansetron, famotidine, and metoclopramide

• Midazolam 2 mg administered prior to leaving holding

INDUCTION

MAINTENANCE OF ANESTHESIA

• Desflurane titrated between 4.2-6.5 %

• NMB maintained with atracurium• Serum glucose assessed Q30

minutes• Regular insulin administered IV in small doses throughout the case as directed by surgeon

IMMUNOSUPPRESSIVE THERAPY

• Induced with methylprednisolone 350 mg IV (15 min)

• Followed by infusion of anti-thymocyte globulin • Infusion rate halved after hypotension noted

• Small boluses of phenylephrine, calcium chloride and ephedrine to maintain MAP ~ 80 mm Hg

• BP stabilizes with 1.5 L of 0.9% NS, 250 mL of 5% albumin, and dopamine infusion at 5 g/kg/min

WE’RE CRUISING…

• Prepare for pancreas graft insertion–Heparin 3,000 units–Mannitol 12.5 g

• Graft inserted• Vascular anastamoses completed• Surgeon announces venous clamp will

be released• Student experiences SEVERE

pudendal neuropathy as this happens……

PANCREATIC REPEFUSION

OVER THE NEXT 80 MINUTES…

• Norepinephrine infusion titrated to 0.25 g/kg/min

• Six 64 g boluses of norepinephrine were administered

• 2L NS bolused to maintain a MAP > 60 mm Hg–Recall, goal MAP ~80 mm Hg

• Diphenhydramine (25 mg) and esmolol (10 mg) administered• No observed response

• Heart rate remained 120 – 140 bpm• Four hours into the case, MAP stabilized at 70

mm Hg• Heparin and mannitol administered prior to

vascular clamping and reperfusion of renal graft• Anesthesia grimaces….

RENAL GRAFT REPEFUSION• MAP acutely fell from 72 to 51 mm Hg after

reperfusion• 128 g norepinephrine bolus administered• Second unit of PRBCs transfused • 10 mg furosemide administered, per the surgeon’s

request• CardioQ SV monitor utilized to assess volume status • 4.5 L of crystalloid infused over remainder of case,• Fluid total: 8 L crystalloid and ~ 1.5 L colloid• Estimated blood loss was 500 mL• A total of three ampules of sodium bicarbonate

were administered to correct acidosis

POST-REPERFUSION SYNDROME

EMERGENCE• By the end of the case, hemodynamics stabilized– Norepinephrine infusion decreased to 0.08 g/kg/min – Dopamine infusion discontinued– Anti-thymocyte globulin infusion reinitiated at full

dose

• NMB antagonized with 0.5 mg glycopyrrolate and 3.5 mg neostigmine after surgical incision closed (fascia left open)

• Patient awoke and followed commands, but was determined to be too weak to safely extubate

• Propofol infusion initiated and patient transported to ICU in stable condition

POSTOPERATIVE COURSE

• Patient was extubated the following morning and transferred out of the ICU two days later

• Patient back to OR for closure of fascia POD 8–Wound infection and edematous pancreas with

multiple necrotic areas discovered

• Returned to OR on POD 12 for I&D and closure of the fascia and skin

• Patient remained hospitalized for one month prior to being discharged to a rehabilitation facility

DISCUSSION

WHO BENEFITS FROM SPKT?• Patients with brittle diabetes and ESRD

• ~ 50-60% of insulin-dependent diabetics develop diabetic nephropathy• Leading cause of renal failure requiring

hemodialysis in young and middle-aged adults in the United States

• While pancreatic transplantation may be indicated for the treatment of disease states such as pancreatitis or cancer, an overwhelming 96% of the total pancreatic transplants in the US are performed in patients with underlying IDDM

(Lin, 2007; Yost & Niemann, 2010; Gruessner, 2011)

SPKT VS. PTA & PAK

(Gruessner, 2011)

WHAT HAPPENS WHEN SPKT FAILS?

• Uncommon• Serious• Few institutions with much experience

(Gruessner, 2011)

PANCREATIC ANASTAMOS

ESDuring bench preparation of pancreatic graft, the bifurcation of donor’s Iliac A. is anastamosed with the Superior Messenteric A. & Splenic A. from graft for ease of anastamosis to recipient’s R Common Iliac A. during transplantation

RENAL ANASTAMOSES

ACS Surgery Principles and Practice

ANESTHESIA CONSIDERATIONS

• Preoperative Assessment, Planning & Collaboration

• Minimizing Consequences of IDDM and ESRD• Glycemic Control• Autonomic Neuropathy• Renal pharmacological considerations

• Management of Immunosuppressive Therapy• Optimization of Graft Function• Fluid Management• Commonly Utilized Intraoperative Drugs• Adequate Graft Perfusion

• Management of Post-Reperfusion Syndrome (PRS)

PREOPERATIVE ASSESSMENT

• Begins with a review of the health history• Special attention to co-existing diseases

that often accompany ESRD and IDDM: • Hypertension, anemia, uremia, and cardiac

disease

• Cardiac workup warranted due to risk for silent ischemia secondary to autonomic neuropathy• Coronary angiography vs. non-invasive testing

such as EKG, TTE, Nuclear Stress Testing, etc

(Garwood, 2008; Evenson & Fryer, 2009; Ouellette, 2010; De Lima, et al., 2003)

PREOPERATIVE LABS

• Laboratory tests should include: CBC, CMP, hemoglobin A1C, coagulation studies, and T&C for at least two units of washed PRBCs

• The transplant workup will also include screening tests for a multitude of infectious diseases, as well as ABO and human leukocyte antigen (HLA) compatibility

(Busque, 2009; Ouellette, 2010)

PREOPERATIVE EXAM• Primary concerns: cardiopulmonary system

and airway • Orthostatics and dialysis details facilitate

estimation of blood volume status • Difficult airway? – Few studies propose intubation difficult in diabetics– Subsequent studies did not substantiate these fears –Nonetheless, prudent to assess joint mobility in

neck and jaw and to prepare for difficult visualization of laryngeal structures

• Identify HD shunts/fistulas and verify adequate padding, as pressure may cause thrombosis

(Yost & Niemann, 2010; Garwood, 2008; Busque, 2009; Palmer, 2010)

GLYCEMIC CONTROL• Many proposed management strategies• Most authors agree BG should be assessed at least Q30-

60 min• Treat with regular insulin IVP or via continuous infusion• Mitigates risk for ketoacidosis, depressed immune

function, decreased wound healing, and worsened neurologic insult in the setting of cerebral ischemia

• Keep BG > 150 mg/dL prior to pancreatic graft insertion• Serum glucose decreases ~ 50 mg/dL/hr after

reperfusion • Hypoglycemia difficult to detect due to anesthesia and

diabetic and renal disease-related neuropathy

• Another complicating factor is routine administration of high-dose corticosteroid for immunosuppressive therapy (Yost & Niemann, 2010; Csete & Glas, 2009; Busque, 2009; Palmer, 2010)

ANESTHETIC TECHNIQUE• Regional anesthesia has been successfully used

for isolated pancreas and kidney transplants• Most authors encourage general endotracheal

anesthesia for the following reasons:– The long, tedious nature of these surgeries– The benefit of muscle relaxation– The potential for hemodynamic instability

• Furthermore, splanchnic perfusion to the transplanted organs is a major concern and the sympatholytic effect of regional anesthesia may pose a danger to adequate graft perfusion

(Hadimioglu, Ertug, Bigat, Yilmaz, & Yegin, 2005; Pichel & Macnab, 2005; Busque et al., 2009; Csete & Glas, 2009; Palmer, 2010; Yost & Niemann, 2010).

IMMUNOSUPPRESSIVE THERAPY

• Transplant function dependent on immunosuppression

• Induction Agents: Started at time of transplantation• May continue for a few doses while maintenance agents

initiated

• Maintenance Agents: Will be continued indefinitely • Commonly encountered induction regimens include

either monoclonal or polyclonal antibodies which may or may not be supplemented with a large dose of corticosteroid

• Regimens vary between patients and institutions• Imperative that anesthetist clarifies schedule and

dosing with transplant team (Csete & Glas, 2009; Evenson & Fryer, 2009; Kaufmann et al., 2002)

SIDE EFFECTS

Miller’s Anesthesia, 7th ed., 2010Clinical Anesthesia, 6th ed., 2009

AUTONOMIC NEUROPATHY

• Diabetics, especially those with ESRD, prone to autonomic neuropathy that may cause:– Gastroparesis increases risk for aspiration– Cardiovascular lability: possible

intraoperative hypotension requiring pressors, dysrhythmias, and bradycardia resistant to atropine

• Regardless of volume status, patients with ESRD often experience exaggerated hypotension with induction of anesthesia

INDUCTION OF ANESTHESIA

• No standard induction drugs specifically contraindicated • May require increased dose of propofol• Titration better than large single bolus

• All patients presenting for SPKT should be considered at risk for aspiration– RSI with cricoid pressure and slight reverse

trendelenberg positioning indicated

NEUROMUSCULAR BLOCKADE

• Succinylcholine usually safe in patients with ESRD• Serum potassium should be < 5.5 mEq/L• 0.6 mEq/L increase in potassium after intubating dose• Increased risk for patients with motor and sensory

neuropathy

• Alternative to succinylcholine for RSI is rocuronium• All short and intermediate acting NDNMBs safe

with careful titration based upon TOF monitoring•  Cisatracurium and atracurium ideal due to

extrarenal metabolism via Hoffman degredation and plasma cholinesterase• Primary metabolite, laudanosine, may cause seizures via

stimulation of CNS at high plasma concentrations

(Busque et al., 2009; Csete & Glas, 2009; Palmer, 2010; Yost & Niemann, 2010; Ouellette, 2010; Ma & Zhuang, 2002 )

MAINTENANCE OF ANESTHESIA

• Balanced anesthetic technique likely best method to sustain hemodynamic stability

• Drugs selected based upon known side effects• N2O often omitted • Morphine and meperidine should also be

avoided due to the action of their metabolites• Desflurane and isoflurane are commonly

used• While the metabolism of sevoflurane has been

implicated in nephrotoxicity, there is a lack of evidence clearly substantiating these concerns

(Yost & Niemann, 2010; Garwood, 2008)

FLUID CHOICES• Multiple considerations• Electrolyte Balance• Edema/Third-Spacing• Acid-Base Balance

• Which Crystalloid?• NS vs. LR vs. Plasmalyte?• NS widely used, but LR and Plasmalyte may be

better

• Which Colloid?• Albumin vs. HES Solutions?• Albumin demonstrated to be best colloid

(O'Malley, Frumento, & Bennett-Guerrero, 2002; Csete & Glas, 2009; Garwood, 2008; Ouellette, 2010; O'Malley et al., 2005; Hadimioglu et al., 2008; Groeneveld, Navickis, & Wilkes, 2011)

MONITORING• Standard ASA monitors placed upon entering

OR • HD catheters may be used if CVC access

warranted– CVP 10 – 15 mm Hg optimizes CO/Renal Blood Flow

• Pulmonary Artery Catheter based upon H&P– Higher filling pressures (>20/15 mm Hg) indicative of better

graft function than lower pressures in one study

• A-Line based upon H&P• Non-invasive cardiac stroke volume monitors

– These have been found to facilitate goal directed fluid therapy

– Demonstrated to PONV, morbidity, and hospital stay(Yost & Niemann, 2010; Csete & Glas, 2009; Busque, 2009; Bundgaard-Nielsen, 2007; Benes et al., 2010)

INTRAOPERATIVE HEMODYNAMICS

• Major hemodynamic shifts are common during organ transplantation

• One illustration of these hemodynamic shifts was provided by a large series that found substantial changes in intraoperative hemodynamics, with hypotension more likely than hypertension (49.6% vs. 26.8%)

(Csete & Glas, 2009)

SPKT HEMODYNAMICS

• Another study following 17 patients presenting for SPKT reported similar hemodynamic shifts

(Mazza, et al., 1998)

POST-REPERFUSION SYNDROME

• PRS was first described by Aggarwal (1987), in the context of orthotopic liver transplantation (OLT)

• A systemic phenomenon generally defined as a 30% decrease in MAP, sustained > 1 minute, occurring < 5 minutes after organ reperfusion

• PRS has been reported in surgeries other than OLT• Cardiopulmonary bypass, aneurysm repair, ischemic limb

reperfusion, and intestinal and renal transplants

• Literature describing incidence of PRS is inconsistent, with rates between 20-55% of all OLT patients and 4% of renal transplants reported

(Bruhl et al., 2012; Chung et al., 2012; Fukazawa & Pretto, 2011; Lomax, Klucniks, & Griffiths, 2010)

PRS PHYSIOLOGY• While the exact mechanism of PRS remains

controversial, some of the initially proposed causes included:• Cold preservation solution into systemic circulation• Acid-base and electrolyte derangements• Release of pro-inflammatory mediators, including nitric

oxide (NO), due to massive induction of oxidative stress

• However, one prospective study found no statistical correlation between serum pH, core temperature, potassium and calcium levels, or arterial blood-gas tensions and PRS

• In the same study, a decreased SVR was the only variable that correlated significantly with PRS

(Bruhl et al., 2012; Chung et al., 2012; Fukazawa & Pretto, 2011; Lomax, Klucniks, & Griffiths, 2010)

PRS PHYSIOLOGY CONTINUED

• Another study exploring PRS hemodynamics found preload was significantly lower in PRS patients than non-PRS patients; despite equal LV function, as observed by TEE

• Acute vasodilation could explain both the decrease in SVR and preload

• Possibly mediated by release of vasoactive inflammatory mediators, secondary to an immunogenic response, resulting in a massive extracellular fluid shift

• Supported by another study that identified increased levels of neutrophil and macrophage activation, with simultaneous anaphylatoxin formation, in patients experiencing PRS

• Another proposed mechanism is the release of ROS (Bruhl, 2012; Yost & Niemann, 2010; Csete & Glas, 2009)

WHY IS PRS IMPORTANT?• PRS implicated in a number of undesirable outcomes:

• Longer mechanical ventilation times and ICU stays, poor graft function, acute organ dysfunction unrelated to the surgical site, and increased mortality

• Bruhl reported a 10% increase in graft failure at six in renal transplant patients experiencing PRS

• The number of post-transplant hospitalization days was almost twice that of non-PRS patients who had the same surgery

• Another study, following OLT patients who developed PRS, reported the relative risk of severe kidney dysfunction to be over three times greater that the non-PRS group

• More frightening, the relative risk of death was determined to be almost three times greater than non-PRS cohorts

(Bruhl, 2012)

WHO IS AT RISK FOR PRS? A significant

correlation was identified between PRS and patients who were either diabetic, Asian, older than 60, or transplanted with an organ from an extended criteria donor

(Bruhl, 2012)

PRS & AUTONOMIC DYSFUNCTION

• Increased prevalence of PRS in patients with autonomic dysfunction

• Both IDDM and ESRD are associated with autonomic dysfunction

• Thus, these pathologies may be good markers for predicting PRS in surgical patients.

(Perez-Pena, et al., 2003)

PRS TREATMENTS?• Unfortunately, there does not yet appear to be a consensus

in the literature regarding effective treatment regimens for PRS

• Proposed strategies include:• Methylene Blue to inhibit inducible NO synthase and scavenge

NO• On retrospective study of 700 patients found methylene blue to have no

effect on changes in MAP, vasopressor or blood transfusion requirements, or end-organ effects

• Prophylactic administration of epinephrine and atropine to attenuate hypotension and bradycardia

• Mannitol to scavenge ROS– Sodium bicarbonate to buffer the increased acid load

• Nonetheless, despite 25 years of research, there remains much to learn about PRS

• However, as more definitive explanations of the mechanism and treatment of PRS emerge, it is reasonable to expect outcomes for a number of surgical procedures to improve

(Bruhl et al., 2012; Busque et al., 2009; Chung et al., 2012; Csete & Glas, 2009; Fukazawa & Pretto, 2011; Ouellette, 2010; Palmer, 2010; Yost & Niemann, 2010)

HINDSIGHT IS 20/20

AREAS FOR IMPROVEMENT

• More proactive/aggressive treatment of N/V• Haldol/droperidol, diphenhydramine, etc

• Tighter glycemic control• Continuous insulin infusion

• Earlier utilization of SV Monitor• Aggressive treatment of early PRS with

Epi?• Fluid Selection• LR only or more balanced ratio of LR/NS

THANK YOU!

QUESTIONS?

pattonc@anest.wustl.edu

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