Perioperative management of isolated pancreas and simultaneous pancreas kidney transplantation

Learning objectives.

By reading this article the reader should be able to:

• •Determine the appropriate preoperative assessment for pancreatic transplant.
• •Describe the basics of intraoperative haemodynamic management specific to pancreas transplantation.
• •Identify the most common complications after transplantation.

Key points.

• •Pancreas transplantation is performed primarily for insulin-dependent diabetes mellitus.
• •Patients present for potential transplant with significant comorbidities in multiple systems.
• •Frequent glucose monitoring is required during surgery and the postoperative period.
• •Increasing postoperative insulin requirements may be a sign of early graft thrombosis.
• •Invasive monitoring should be used during surgery as haemodynamic instability is common and can occur rapidly.

According to the most recent data, ∼463 million adults are living with diabetes mellitus (DM), of whom ∼10% suffer from type 1 DM.¹ The prevalence of DM in the USA in 2018 was ∼10.5% (34.2 million Americans) of whom 4.6% are insulin dependent (1.6 million patients).² Total annual medical costs in 2017 were estimated at $327 billion just for the USA, with >70% of these costs in direct medical care.²

The first pancreas transplantation (PT) was performed in 1966 in Minneapolis, USA and since then >19,000 PTs have been performed worldwide. Pancreas transplantation can be performed as isolated transplantation (PT), after kidney transplantation (PAK) or simultaneously with a kidney transplantation (SPK). Type 1 DM is the predominant indication for PT, most of which are performed as SPK (76.6%). In haemodialysis-dependent patients, SPK is associated with a 30% reduction of mortality compared with non-transplanted patients who remain on dialysis.³ Patient and graft survival rates for SPK are similar to living donor kidney transplantation. However, compared with recipients of deceased donor kidneys, survival rates are higher, especially in patients aged >45 yrs.⁴ In the absence of kidney transplantation, the American Diabetes Association recommends PT for patients meeting the following three criteria:⁵

• •A history of frequent, acute and severe metabolic complications requiring medical attention.
• •Clinical and emotional problems with exogenous insulin therapy that are so severe as to be incapacitating.
• •Consistent failure of insulin-based management to prevent acute complications.

Other indications for PT include type 2 DM, chronic pancreatitis and malignancy requiring pancreatectomy (intraductal papillary mucinous neoplasm of pancreas, neuroendocrine tumours of pancreas).⁶ Recipients are selected carefully. Typically, patients are aged <60 yrs with a BMI <35 kg m⁻².⁶ Waiting list numbers in the USA increased slightly in 2019. Fig 1, Fig 2 show USA and worldwide SPK and isolated pancreas transplants by year.⁷ Around 50% of patients are on the waiting list for <90 days at any time, and median time to transplantation is 12 months.⁷

Fig 1.

Transplants by year in the United States: 1990–2018.⁷

Fig 2.

International regional pancreas transplants by year 2000–20.

Both PT and SPK procedures require specific management of anaesthesia and are associated with procedure-specific complications. It is therefore imperative that these patients are screened and their condition optimised before, carefully monitored during and managed effectively after surgery to provide the best outcomes.

Preoperative evaluation

The predominant challenge associated managing patients undergoing PT is poorly controlled and often longstanding DM, which is associated with protein glycosylation, accelerated atherosclerosis and as a consequence micro- and macroangiopathy resulting in significant end-organ damage. Therefore most of the preoperative evaluation should focus on identifying signs of end-organ damage secondary to DM, as cardiovascular complications are the most common cause of morbidity and mortality after transplantation. The prevalence of coronary artery disease is four times higher compared with non-diabetic patients, and the incidence of perioperative cardiac events may exceed 10%.⁸

As with any preoperative evaluation, a careful medical history and physical examination is mandatory. Assessment of glycaemic control with measurement of glycated haemoglobin HbA_1C, metabolic equivalents and signs of peripheral vascular disease are key for preoperative optimisation and improving postoperative outcomes. Signs of autonomic dysfunction such as orthostatic hypotension or a decrease in beat-to-beat heart rate variability may predict a difficult intraoperative course.⁹ These patients may present with exercise intolerance because of reduced response in heart rate and arterial pressure during exercise.¹⁰ Patients with autonomic neuropathy undergoing anaesthesia may experience significant haemodynamic instability. There is a higher incidence of intraoperative bradycardia, hypotension and cardiopulmonary arrest.¹¹ Therefore a 12-lead ECG should be routine in addition to assessment for orthostatic hypotension. Additional cardiac investigations (exercise or dobutamine stress test; adenosine thallium or myocardial perfusion scan) are often performed to screen for ischaemia and cardiac reserve capacity. A negative stress test is associated with a low risk of perioperative myocardial infarction and cardiac death.¹² A positive test necessitates coronary angiography. Right heart catheterisation should be considered if there are concerns about cardiac function, filling pressures and pulmonary hypertension.¹³

As with any patient undergoing anaesthesia, examination of the airway should be performed before induction of anaesthesia. Diabetic patients have a higher incidence of obesity and ‘stiff joint syndrome’, both of which can increase the likelihood of a difficult airway.⁸ Despite this, most patients with severe diabetes undergoing organ transplantation do not require extraordinary techniques to perform successful intubation.¹⁴

Impaired respiratory function and lung disease can occur in patients with DM as a result of microangiopathy of pulmonary capillaries, autonomic neuropathy and changes in collagen. These changes can the lead to decreased basal tone of bronchi, decreased lung compliance with decreased pulmonary volumes, decreased carbon dioxide diffusion capacity, decreased cough sensitivity and increased risk of respiratory infections. Although pulmonary function testing is not required before transplantation, it may be helpful if there are concerns about overall pulmonary function.¹⁵ Preoperative incentive spirometry use and physical exercise can be useful to help prevent postoperative pulmonary complications.

All patients should have routine laboratory testing before anaesthesia. Chronic renal failure is often characterised by anaemia, resulting in reduced oxygen-carrying capacity and increased cardiac output. In cases of anaemia, underlying causes such as iron deficiency should be clarified and corrected if needed. Iron infusions have been shown to be safe and effective, with a very low risk of anaphylaxis or anaphylactoid reactions, which were more common in older formulations of high-molecular-weight iron dextran (HMW-ID).¹⁶ In patients with severe anaemia resistant to treatment, erythropoiesis-stimulating agents may be needed, though complete correction of anaemia can be associated with increased cardiovascular events.¹⁷ More information regarding treatment of anaemia is available in the KDIGO Clinical Practice Guidelines for Anemia in chronic kidney disease (CKD).¹⁸ In addition, coagulation disturbances may be present in patients with CKD. Some patients may experience excessive bleeding episodes while others may be prone to thromboembolic complications. The reason for this is unclear.¹⁹ Pancreas transplant recipients with type 1 DM are more likely to present with hypercoagulability, caused by disturbances in multiple components of clot formation.²⁰ Point-of-care testing such as thromboelastography (TEG) or rotational thromboelastometry (ROTEM) may be helpful in determining underlying coagulation disturbances.

A blood type and crossmatch should be performed to ensure availability of blood products. In patients receiving SPK who are on either peritoneal or haemodialysis, enquiry regarding last dialysis should be made. Patients may present with volume overload or electrolyte/acid base abnormalities if a dialysis session is missed. These patients may require dialysis before transplantation.

Immunosuppression

Immunosuppressive therapy is mandatory in any transplant procedure. Most regimens include induction immunotherapy, with agents such as rabbit or equine antithymocyte globulin (ATG, Thymoglobulin), monoclonal anti-CD-25 (basiliximab or daclizumab) or T-cell-depleting antibody (alemtuzumab). The choice of agent depends on centre preferences and the patient's characteristics. Induction immunotherapy does not have a clear benefit to patient or graft survival but does reduce the rate of early rejection episodes and enables steroids to be weaned earlier.²¹ Maintenance therapy typically consists of mycophenolate mofetil, calcineurin inhibitors and steroids, with early or delayed withdrawal of corticosteroids.²²

Surgical techniques

Pancreas allografts are typically acquired from donation after brain death (DBD) donors and donation after circulatory death (DCD) deceased donors. Donors are often <50 yrs old, and generally healthy with normal amylase concentrations and normal HbA_1C. Obese donors are often declined because the incidence of graft pancreatitis is increased.²³ In SPK, the pancreas allograft is transplanted first because a shorter cold ischaemia time (<12 h) is tolerated compared with that for the kidney (<24 h). Surgical technique involves placing the graft either intraperitoneally or extraperitoneally. Intraperitoneal placement occurs via a midline incision. Donor duodenum is anastomosed to proximal jejunum or distal ileum. Donor vessels are anastomosed end to side with recipient's vessels (superior mesenteric artery or splenic artery, portal vein or inferior vena cava). In a newer technique, the pancreas allograft may be placed in the right retrocolic gutter and duodenoduodenostomy is performed. Extraperitoneal pancreas placement typically involves placement in the iliac fossa, usually on the right as the anatomical location of the iliac vessels is more favourable. This allows for systemic bladder drainage. The donor duodenum is anastomosed to the vesical dome. Donor vessels are anastomosed to iliac vessels.²⁴

Intraoperative management

Monitoring

All recipients should have reliable peripheral i.v. access that is adequate for volume resuscitation and blood transfusion. Central venous access may be needed to allow infusions of vasopressor medication or for antirejection medications. Pulmonary artery catheter monitoring is typically not indicated. Arterial catheterisation is recommended but not strictly necessary. Its benefits include monitoring of large haemodynamic swings, electrolyte/acid base status and blood volume/volume status.

Induction and maintenance of anaesthesia

Various agents can be used for the induction and maintenance of anaesthesia, all with the goal of haemodynamic stability. Patients with autonomic neuropathy may have a higher risk of pulmonary aspiration during induction because of diabetic gastroparesis, a form of autonomic neuropathy resulting in delayed gastric emptying.²⁵ A rapid-sequence induction may be needed to avoid aspiration in patients with gastroparesis. Typically, anaesthesia can be maintained with a combination of volatile anaesthetic agents, opioids and neuromuscular blocking agents. Volatile anaesthetic agents may be preferred to i.v. anaesthesia because of their potential beneficial effects in alleviating ischaemia-reperfusion injury.²⁶ When considering inhalation agents there may be a slight preference for sevoflurane or desflurane over isoflurane, as they lead to lower peak postoperative amylase and lipase concentrations, though clinical outcomes do not differ significantly.²⁷ Opioids should be carefully titrated to the desired effect, as patients with end-stage renal disease (ESRD) and azotaemia can have a significant reduction in both clearance and volume of distribution of fentanyl.²⁸ The type of opioid used is frequently centre specific. Despite the pharmacokinetic variability of fentanyl and its analogues they have relatively inactive metabolites and minimal haemodynamic effects compared with opioids such as pethidine (meperidine) or morphine, which have active metabolites that depend on renal clearance. Remifentanil and sufentanil are also good options.

Neuromuscular blocking agents

The choice of neuromuscular blocking agent for tracheal intubation should be carefully considered, based on the serum potassium. If hyperkalaemia is not a concern, then a depolarising agent such as suxamethonium can be considered, though a non-depolarising agent is preferred at most centres. Suxamethonium is best avoided in patients with CKD but can be used in patients undergoing PT. Historically neuromuscular blocking agents that were eliminated through Hoffman degradation or plasma esterases (atracurium, cisatracurium) were preferred in SPK as they were not affected by renal dysfunction. Rocuronium is increasingly being used, as sugammadex has been shown to be safe in renal transplant candidates; this is because it is excreted by the allograft kidney once it starts functioning or through dialysis. The use of sugammadex remains controversial because of its off-label use in severe renal impairment and higher cost in some countries.²⁹

Pain management

Various methods of perioperative pain management can be used. A multimodal approach is preferable with paracetamol (acetaminophen) as a first component. A neuraxial technique is a good option when the pancreas graft is sited within the abdomen and there are no contraindications such as hypocoagulability. If the patient is at risk for thrombosis, thromboembolic prophylaxis may be warranted soon after surgery, as graft thrombosis is a dreaded complication. This may present difficulty regarding removal of an epidural catheter but is not an absolute contraindication to neuraxial analgesia. Preoperative multidisciplinary consultation can help clarify the risks and enable a balanced decision. Other regional techniques that have varying degrees of success are erector spinae plane blocks (ESPs), paravertebral blocks, transversus abdominus plane blocks (TAPs), rectus sheath blocks, quadratus lumborum (QL) or i.v. lidocaine infusions. A combination of low-dose opioids and local anaesthetic may be helpful in epidural anaesthesia to decrease the dose of systemic opioids required, both during and after surgery. Yeap and colleagues found that standard opioids provided superior pain control in the post-anaesthesia care unit (PACU) but patients with TAP catheters and TAP liposomal bupivacaine needed lower doses of opioids and had faster times to return of bowel function.³⁰ Kolacz and colleagues found QL blocks may be more effective than TAP blocks.³¹ Hausken and colleagues found that rectus sheath blocks could provide equivalent analgesia compared with thoracic epidurals.³² I.V. opioids may be used in the absence of neuraxial or regional techniques.

Fluids and haemodynamics

Intraoperative haemodynamic monitoring is imperative. Retrospective data have shown that a mean arterial pressure (MAP) ≤70 mmHg in addition to low volume repletion (central venous pressure [CVP] <8 mmHg) was associated with delayed graft function. An MAP ≥91 mmHg and CVP ≥12 mmHg was associated with immediate graft function and better long-term survival.³³ The optimal MAP in transplantation remains unknown. A large meta-analysis has shown that CVP is a poor marker for fluid responsiveness and is not recommended to guide fluid resuscitation.³⁴ The use of dynamic metrics, such as pulse pressure variation and stroke volume variation, is becoming more prevalent. These can be derived from several monitoring systems that deliver continuous data output based on the arterial waveform. Guidelines on targets to aim for are currently lacking. Other available non-invasive cardiac output monitors include oesophageal doppler systems and bioimpedance monitors, but each has its benefits and limitations.

Traditionally, 0.9% sodium chloride (normal saline) was used as this avoided any additional potassium in balanced solutions. However, large amounts of normal saline should be avoided, because they can cause hyperchloremic acidosis which can impair kidney function and be accompanied by hyperkalaemia.³⁵ Several studies have shown that balanced crystalloid solutions such as Ringers' lactate, Plasmalyte or Normosol, improve acid–base profiles and are associated with lower serum potassium secondary to improved kidney function.^35,37Albumin and starches have not been shown to have any benefit over crystalloid solutions, and synthetic starches have been associated with worse renal outcomes in critically ill patients.³⁴

Vasopressor drugs may be needed to maintain an adequate arterial pressure. The ideal vasopressor for this remains unknown but noradrenaline (norepinephrine) is often used. Historically, dopamine has been advocated and used for its vasoactive and reported renal protective effects, but studies have been conflicting and patients' responses to dopamine are variable, depending on renal vascular resistance. The empirical use of dopamine is therefore no longer recommended.³⁷ Vasodilator drugs are not used commonly. Fenoldopam, a selective dopamine (DA₁) receptor agonist, has been shown to decrease renal vascular resistance and the incidence of acute kidney injury (AKI) after major surgeries, but with no impact on the need for renal replacement therapy or mortality. Studies on fenoldopam are variable in method and definition, clinical outcomes are lacking and there are no data in patients undergoing PT.³⁶

Mannitol is frequently given before reperfusion of the allograft. In some studies, mannitol has been associated with a reduced incidence of postoperative renal failure or delayed graft function, but solid evidence is lacking. The exact underlying mechanism is unknown but could result from decreasing cellular oedema as a result of ischaemia-reperfusion injury, or its action as a free radical scavenger.³⁸ Furosemide can be given, often at the surgeon's discretion, either immediately before or after reperfusion; it is used to promote diuresis of the new kidney graft but does not correlate with graft survival.³⁹

Reperfusion of both organs can be associated with hypotension. Causes include bleeding, reduction in preload secondary to unclamping of the iliac artery, and/or ischaemia-reperfusion injury. Prolonged ischaemia increases the extent of reperfusion injury and increases the risk of hyperkalaemia because of increased lactate formation. Hyperkalaemia can reflect in peaked T-waves on ECG and cardiac arrythmias. These should be immediately identified and treated. Treatment of hyperkalaemia can include multiple agents including i.v. insulin with glucose, beta-agonists, bicarbonate and loop diuretics. Calcium chloride 1 g is advised to stabilise the membrane potential of cardiac myocytes when serum K⁺ is >6.5 mmol L⁻¹, or when >6.0 mmol L⁻¹ with ECG changes.⁴⁰ Hypotension is best treated with fluids and vasopressors as needed.

Glucose regulation

Intraoperative glucose management is extremely important in PT and SPK. Before surgery patients are often provided with glucose i.v. and supplemental insulin via bolus regimens or with continuous infusion. Continuous infusions of insulin should be stopped at reperfusion as the transplanted reperfused pancreas takes up insulin production quickly.⁴¹ The timings of glucose measurements depend on institutional protocol after pancreas reperfusion, but they can be as frequently as every 5–15 min and not less than every 60 min until normoglycaemia has been achieved and maintained. Hypoglycaemia is possible and can lead to significant morbidity and mortality if not recognised promptly. Delayed normoglycaemia can reflect graft dysfunction, delayed graft function, rejection, pancreatitis or insufficient donor-to-recipient size.

Antibiotic and antifungal therapy

Antimicrobial prophylaxis is standard of care as patients are immunosuppressed. The regimen varies between institutions but usually comprises a first-generation cephalosporin (mostly commonly cefazolin), with or without a nitroimidazole such as metronidazole.⁴² Surgical site infections occur in 9–45% of patients undergoing PT. Risk factors include prolonged surgical time, increased ischaemia times, enteric drainage, post-transplant fistula, manual anastomosis, blood transfusion, older donor (>55 yrs old) and acute tubular necrosis or graft rejection.⁴³

Anticoagulation

Graft thrombosis is a common complication and is addressed below. Anticoagulant therapy is often started in the early postoperative period, usually with a combination of platelet aggregation inhibitors and low-molecular-weight heparin. Although anticoagulant therapy increases the risk of bleeding complications and reoperation, it decreases the risk of early thrombosis.⁴⁴

Postoperative management

Patients are usually monitored in the ICU for glucose, electrolyte and arterial pressure monitoring after surgery. Maintaining normotension is important: hypertension can increase myocardial oxygen demand and lead to disruption or leakage of the vascular anastomoses, whereas hypotension can lead to poor graft perfusion and failure. Multimodal pain control is important to decrease physiological stress, avoid large doses of opioids and improve patients' satisfaction. Blood glucose is monitored according to the local institutional protocol. A typical protocol may include hourly glucose checks for the first 24 h, then every 2 h for the second 24 h, and finally every 4 h for the third 24-h period. After the first 3 days, blood glucose can be checked every 6 h. Two different insulin replacement styles have been described, first is complete insulin replacement with the goal of resting the pancreas allograft for 3–4 days and maintaining euglycemia. Complete replacement can be difficult and blood glucose is often erratic secondary to the stress of surgery, level of insulin resistance and tapering doses of steroids. Insulin replacement as needed allows the allograft to self-regulate: blood glucose is measured every 1–2 h and insulin doses adjusted as required. A sudden increase in requirements for exogenous insulin is a signal of dysfunction of the allograft and warrants immediate graft assessment. Hyperglycaemia can be a sign of rejection that is associated with low probability of reversal.

Complications

Graft thrombosis

The reported rate of re-exploration in PT is between 14% and 65% within the first 3 months. More than 70% of early graft losses can be attributed to technical failure, not rejection. These include graft thrombosis, bleeding, infection, pancreatitis, anastomotic leak and pancreatic fistula of which graft thrombosis is the most frequent technical cause of graft loss.⁴⁴ To prevent graft thrombosis, anticoagulant therapy is frequently started in the early postoperative period. Partial thrombosis is more common than complete thrombosis, and venous thrombus is three times more common than arterial thrombosis.⁴⁴ Early thrombosis usually occurs within 48 h but can occur up to 6 weeks after transplantation. Bleeding complications can be intra-abdominal and are often related to anticoagulation. Gastrointestinal bleeding from intestinal anastomosis or staple lines is often self-limiting. Early pancreatitis is most often related to ischaemia-reperfusion injury and occurs in 10–20% of patients within the first 48 h after transplant. At a later stage, pancreatitis can be related to rejection, and can lead to abscess, necrosis, fistulas, pseudocysts or thrombosis.⁴⁴ Per the Organ Procurement and Transplantation Network (OPTN) and the United Network for Organ Sharing (UNOS), pancreas graft failure is considered when any of the following occurs: the recipient is listed for a repeat PT; the recipient's transplanted pancreas is removed; the recipient registers for islet transplant after receiving pancreas transplant; a recipient's total insulin use is ≥0.5 units kg⁻¹ day⁻¹ for 90 consecutive days; or the recipient dies.

Acute rejection

Acute rejection is a greatly feared complication. Acute cellular rejection (T-cell-mediated) (ACR) is common within the first 3–6 months after transplant. The prevalence varies between 5% and 20% depending on the patient's immunological profile and the type of immunosuppression. Risk factors include: calculated panel reactive antibodies (cPRA) >20%; degree of human leukocyte antigen (HLA) mismatch; African American race; T-cell-positive cross match; and non-compliance with medications. Treatment of rejection is based on acuity, severity, risk factors and the cause (if known). Typically, treatment consists of high-dose steroids and increasing immunosuppressive drugs based on the patient's current regimen, but can include additional doses of thymoglobulin, and antimicrobial prophylaxis. Antibody-mediated rejection (AMR) is seen in 10–30% of immunologically high-risk patients, and is treated aggressively with plasmapheresis, steroids and rituximab as per institutional protocol.

Transplant data and outcomes

OPTN tracks data across the USA regarding transplants (Fig. 1). From 1988 to April 2021, there have been 25,734 SPK transplants and 9079 isolated pancreas transplants. SPK transplants peaked in 1998 with 972 performed, and remained at ∼900 per year through the early 2000s. SPK transplants decreased in 2014 when only 709 were performed, but have since increased. The number of isolated pancreas transplants peaked in 2004 at 603 but has since decreased annually with only 135 performed in 2020.⁷

An analysis of >21,000 pancreas transplants from the International Pancreas Transplant Registry found that the 5-yr and 10-yr graft function rates were 73% and 56% for SPK, 64% and 38% for PAK, and 64% and 38% for PT. Five-year survival for SPK was almost 90%, while 10-year survival was 76%.³³ Waiting list times as of 2018 were 13.5 months for SPK and 19.7 months for isolated pancreas.³⁷

Conclusions

Isolated pancreas and combined kidney-pancreas transplantations present several unique challenges in the perioperative period. End-organ dysfunction secondary to DM make these patients prone to intraoperative and postoperative complications. Careful monitoring, haemodynamic stability, glucose control and avoidance of electrolyte disturbances are need for optimal graft outcome. Invasive haemodynamic monitoring, adequate fluid management and frequent laboratory analyses are recommended. Patients' survival and graft survival have improved greatly over the past 20 yrs and we hope to continue to improve. Vigilance and anticipation of potential problems at each stage of the transplantation will protect the patient from potential morbidity and mortality intraoperatively and after surgery.

Declaration of interests

The authors declare that they have no conflicts of interest.

MCQs

The associated MCQs (to support CME/CPD activity) will be accessible at www.bjaed.org/cme/home by subscribers to BJA Education.

Biographies

AishaP.Ullah MD is clinical assistant professor of anaesthesiology and perioperative medicine specialising in transplantation anaesthesiology at University of Pittsburgh Medical Center (UPMC). She is active in residents' education.

Michael S. Trostler MS MD is assistant professor of anaesthesia at Virginia Commonwealth University. He completed an abdominal transplant fellowship at UPMC focusing on liver transplantation.

Ezeldeen Abuelkasem MSc is assistant professor of anaesthesiology and perioperative medicine specialising in transplantation anaesthesiology, cardiovascular physiology and the diagnosis and management of coagulation disorders. He has won multiple ‘best teacher of the year’ awards by residents at UPMC and is director of echocardiography education.

Raymond M. Planinsic MD FASA is chief of transplantation anaesthesiology at UPMC and professor of anaesthesiology and perioperative medicine at the University of Pittsburgh School of Medicine. He is an internationally recognised expert in the field of transplantation anaesthesiology, has published extensively and is a frequent invited speaker at national and international meetings.

Matrix codes: 1I05, 2A04, 3A03