ANESTHESIA CONSIDERATIONS FOR SIMULTANEOUS PANCREASKIDNEY 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 ANASTAMOSES During 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 Clinical Anesthesia, 6th ed., 2009 Miller’s Anesthesia, 7th ed., 2010 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! 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