Peritoneal surface oncology is a rapidly evolving subspecialty that manages a group of neoplasms collectively termed peritoneal surface malignancies. Clinically, this group of malignancies is categorized into peritoneal carcinomatosis secondary to abdominal, pelvic, or extraabdominal malignancies; pseudomyxoma peritonei; and primary peritoneal tumors.1 Current treatments combine cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemoperfusion (HIPEC).2–5 In our opinion, there is insufficient information available within the anesthesiology literature to educate anesthesiologists on the goals and objectives of the operation, the anticipated metabolic and physiologic derangements, and the potential chemotherapeutic toxicities. In this article, we present an overview of the current literature as well as the anesthetic considerations and perioperative management of the patient undergoing CRS and HIPEC for peritoneal surface malignancies.
PERITONEAL SURFACE MALIGNANCIES
Peritoneal surface malignancies are categorized as peritoneal carcinomatosis, pseudomyxoma peritonei, or primary peritoneal tumors.1
Peritoneal carcinomatosis is a tumor that spreads over the peritoneal surfaces secondary to gynecologic (frequently ovarian tumors) and nongynecologic tumors (frequently gastric and colorectal cancer) that seed the peritoneum. Although the use of HIPEC is still rare, these diseases are not.2,6 There are 20,000 ovarian carcinomas in the United States per year, 60% presenting as stage III or IV (most of these with carcinomatosis),7 and 140,000 colorectal cancers in the United States per year, approximately 10% presenting with carcinomatosis.7 Nongynecologic tumors that metastasize to the peritoneum are usually gastrointestinal in origin, with gastric cancer and colorectal cancer being the more common causes of secondary peritoneal carcinomatosis.2,6 Median survival rates in patients with untreated peritoneal carcinomatosis are less than 7 months for nongynecologic tumors and less than 15 months for gynecologic tumors.8
Pseudomyxoma peritonei is a rare disease that frequently arises from mucinous appendiceal tumors and is characterized by mucinous ascites and peritoneal implants.6,9–12 This cancer often presents with progressive abdominal distention caused by the accumulation of mucinous ascites. Five-year survival rates are improved with CRS and HIPEC treatment compared with treatment with systemic chemotherapy alone (86% vs 44%).11
Primary peritoneal tumors are usually diffuse malignant peritoneal mesotheliomas, an uncommon yet fatal group of cancers that account for 10% to 30% of all mesotheliomas diagnosed in the United States with up to 400 new cases in the United States every year.1,5,13,14 Median survival rates range from 9 to 15 months in patients with these mesotheliomas who are treated with palliative surgery with or without systemic chemotherapy.14
Successful management of patients who have peritoneal surface malignancies with CRS and HIPEC involves assessment of the extent of systemic disease via positron emission tomography and computerized tomography scans of the chest, abdomen, and pelvis.15 In the setting of peritoneal carcinomatosis of colorectal origin, patients with fewer than 3 small hepatic metastases, absence of biliary obstruction, and a successful response to systemic chemotherapy are the most optimal candidates for CRS and HIPEC.15 Selection criteria for CRS and HIPEC include medical optimization with no active cardiac conditions as defined by the American Heart Association guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery; absence of extraabdominal disease, extensive hepatic metastases, and significant retroperitoneal disease; age younger than 70 years; and peritoneal disease that is either amendable to complete or near complete resection.16–18
CRS, a group of parietal and visceral peritonectomy procedures, is performed in series or during a single operation to excise intraabdominal macroscopic tumors.12,15,19,20 CRS can range from an isolated omentectomy to complete resection of multiple abdominal organs, including the gastrointestinal tract, pancreas, spleen, gallbladder, uterus, ovaries, and portions of the liver.19,21 The peritoneal cancer index, determined at the time of abdominal exploration, estimates the success of CRS and 5-year survival rates.22 Similar to other assessments of carcinomatosis, this index attempts to categorize the extent of tumor involvement.23 Removal of all macroscopic tumors is not always possible. Therefore, the ultimate surgical goal is to debulk the majority of tumors until the nodules are 2.5 mm to ensure that cytotoxic drugs will penetrate those that remain.11,24,25
Hyperthermic Intraperitoneal Chemotherapy
Directly infusing chemotherapeutic drugs into malignant effusions was described in 1955 when mustard nitrogen was injected into pericardial and peritoneal effusions.26 In 1977, the effects were reported regarding the use of hyperthermic peritoneal perfusion with sterile normal saline warmed to 41°C.27
The goal of intraperitoneal perfusion of chemotherapeutic drugs is to maximize exposure of the involved tissue to high concentrations of chemotherapeutic drugs (20–1000 times greater than plasma levels), while minimizing exposure of the normal tissue.2,28–30 HIPEC drugs are high-molecular-weight hydrophilic drugs that are unable to cross the peritoneal fluid–plasma barrier and demonstrate slow peritoneal clearance.31–34
Through inhibition of DNA repair mechanisms, denaturing of proteins, and activation of heat shock proteins, hyperthermia not only exhibits a direct cytotoxic effect but also causes an immune-mediated attack on tumor cells.35,36 HIPEC is most successful in treating tumors when the perfusion is administered immediately after CRS and before any gastrointestinal tract reconstruction to prevent enclosure of malignant cells within scar tissue, adhesions, or anastomosis sites.37,38
Typically, HIPEC is performed with a closed abdominal technique in which a suprahepatic inflow cannula and a pelvic outflow cannula are connected through a recirculating perfusion circuit driven by a roller pump heat exchanger.39 Perfusion of cytotoxic drugs for 60 to 120 minutes is followed by abdominal lavage, drainage, and abdominal closure.21,30,32 An open technique can also be performed whereby the abdomen remains open during chemoperfusion. In absence of peritoneal cavity expanders, leaving the abdomen open may prevent an increase of intraabdominal pressure and the associated complications including decreased renal perfusion. Another advantage is that perfusate is not reused and therefore there is less spreading of tumor cells throughout the cavity.21 However, open techniques also increase risk of exposure of chemotherapeutic drugs to operating room personnel.40
The anesthesiologist should be familiar with the toxicity profiles of the various chemotherapeutic drugs (Table 1) and understand how the type and volume of carrier fluid affects the pharmacokinetics and ultimately the systemic absorption of these cytotoxic drugs. The carrier solution for HIPEC is dependent on the cytotoxic drug used for chemoperfusion. Currently, the solutions of choice are either isotonic saline or dextrose-based peritoneal solutions. Of the currently used drugs, only oxaliplatin is used in 5% dextrose-based water solutions because the presence of chloride ions degrades oxaliplatin into less-cytotoxic metabolites.41,42 Although most centers use 1.5% dextrose isotonic peritoneal dialysis solutions, some institutional protocols suggest regular crystalloids such as lactated Ringer’s solution.37 These isotonic low-molecular-weight solutions are readily absorbed from the peritoneal cavity, resulting in both an uneven distribution and varied concentration of cytotoxic drugs in the peritoneal cavity because of the loss of carrier solution.32,43 However, given the short duration of HIPEC and the ability to adjust flow rates intraoperatively, the role of carrier solutions becomes less important.32 Alternative carrier solutions are currently being investigated. Animal studies using high-molecular-weight, isomolar glucose polymer solutions such as hetastarch demonstrated a prolonged exposure of intraperitoneal tumor cells to cytotoxic drugs.32,44 The systemic absorption of 5% dextrose solutions can lead to severe hyperglycemia and hyponatremia. In contrast to animal studies, human studies using hypotonic solutions failed to demonstrate increased tumor cell penetration. Patients in this study had an increased incidence of intraperitoneal hemorrhage and thrombocytopenia compared with patients treated with hypertonic solutions.45
Preoperative Anesthetic Management
Anesthesiologists face several perioperative challenges when patients with peritoneal surface malignancies need surgery. Surgical and anesthetic management are complicated by systemic absorption of peritoneal fluid, with blood loss, acute kidney injury, electrolyte abnormalities, ascites, hypothermia, and hyperthermia. Physiologic perturbations during the perioperative period may precipitate multisystem organ failure.
The cardiac risk of patients undergoing CRS is comparable to the risk for patients who undergo other types of major abdominal surgery.46,47 Cardiopulmonary assessment should focus on the ability of the patient to compensate for the anticipated physiologic derangements, including tachycardia, increased cardiac index, and increased oxygen consumption.48,49 Electrolyte, blood urea nitrogen, creatinine, albumin, bilirubin, and complete blood count levels, as well as coagulation variables and glucose values, should be obtained.
Patients of advanced age or those with risk factors may undergo cardiopulmonary testing as guided by the American College of Cardiology/American Heart Association guidelines for patients undergoing noncardiac surgery.18 The goals of patient selection include identifying patients with multiple comorbidities that contribute to unacceptably high perioperative mortality rates.
Preoperative renal assessment in the form of calculated glomerular filtration rate identifies patients at risk for postoperative renal injury. Although acute kidney injury from HIPEC may be reversible,21 patients with preoperative renal dysfunction are at increased risk for perioperative cardiovascular events.50
Intraoperative Anesthetic Management
Temperature Management The carrier solution for HIPEC is heated to 40°C to 43°C, putting the patient at significant risk for hyperthermia. Hyperthermia may cause consumptive coagulopathies, arrhythmias, liver/renal injury, peripheral neuropathies, and seizures.35 Before initiation of HIPEC, controlled hypothermia (decreased room temperature, avoiding surface air heating, cool IV fluids) should be used to avoid severe hyperthermia. The risks of hypothermia include alteration of pharmacokinetics of frequently used anesthetic drugs and increased risk of blood loss, surgical wound infections, and adverse myocardial events.51 Therefore, temperature management weighs the risks of hypothermia versus those of hyperthermia.
Cardiovascular Management Patients undergoing total body hyperthermia for treatment of metastatic cancer demonstrate increases in heart rate, cardiac index, and oxygen consumption, as well as decreases in systemic vascular resistance.52 Plasma norepinephrine levels were found to increase linearly parallel to the core body temperature.52
In addition to the monitors recommended by the American Society of Anesthesiologists, a radial arterial catheter is placed for frequent blood sampling. Pulse pressure variation, calculated from the invasive arterial tracing, can be used to assess fluid responsiveness.53 Central venous access may be established to administer vasoactive medications. Central venous pressure monitoring does not reliably measure blood volume or change in blood volume.54
Elevated Abdominal Pressures During intraperitoneal chemoperfusion, perfusate is used to circulate cytotoxic drugs throughout the peritoneal cavity. As the abdominal cavity fills with chemotherapeutic drugs dissolved in carrier fluid, the abdomen becomes distended and parallels physiologic changes found during pneumoperitoneum (compression of the inferior vena cava and decreased preload).40 Depending on perfusion flow rates, volume of perfusate, and surgical use of peritoneal expanders, intraabdominal pressures can vary between 12 and 26 mm Hg.55 The goals are to maintain adequate abdominal perfusion pressure(>60 mm Hg) by increasing the mean arterial blood pressure either through increasing cardiac output by augmenting preload with a normal to slightly increased intravascular volume or by increasing the systemic vascular resistance with vasoactive medications.40,56–58 Additionally, maximizing abdominal relaxation with muscle paralysis is also useful.57,58
Metabolic Response The severity of metabolic changes observed during HIPEC depends on the type of carrier solution and degree of hyperthermia. Hyperthermia increases metabolic activity, heart rate, carbon dioxide production, and ultimately oxygen consumption.40 In contrast to patients who receive HIPEC with lactated Ringer’s solution, patients who receive HIPEC with a 5% dextrose solution may experience hyperglycemia, hyponatremia, and metabolic acidosis.59 Studies report increases of 2 to 4 mmol/L lactate.60 These metabolic changes occur when both glucose and free water are absorbed into the plasma causing hyperglycemia and dilutional hyponatremia. The latter is also due to the excretion of sodium into the peritoneal fluid in patients treated with oxaliplatin.59 Although these changes do not normally lead to increased morbidity and mortality, a few case reports have documented cerebral edema due to severe hyponatremia.59 Hypervolemic hyponatremia can be managed with IV furosemide whereas euvolemic and hypovolemic hyponatremia secondary to peritoneal extraction of sodium and water may be slowly corrected with IV saline replacement. The hyperlactatemia observed during HIPEC procedures may be from type B lactate production, where the increase is a result of hyperglycemia-induced glycolysis rather than type A lactate production, which is due to tissue dysoxia or hypoperfusion.59,60 Intraoperative arrhythmias from cisplatin-induced renal wasting of intracellular magnesium have been reported.61
Fluid and Renal Management Among patients undergoing CRS with HIPEC, 1.3% to 5.7% develop acute kidney injury from nephrotoxic chemotherapeutic drugs, abdominal hypertension, and large fluid shifts resulting in significant intravascular volume depletion.62–64 Renal failure associated with HIPEC is multifactorial, is normally reversible, and is usually associated with use of cisplatin.21,64 A correlation between HIPEC doses of cisplatin >240 mg and increased postoperative serum creatinine levels has been reported.64 When used systemically, mitomycin C has been shown to cause mesenchymal endothelial cell damage, leading to nephrotoxicity.64
Two large-bore peripheral IV catheters should be placed for fluid resuscitation where large, highly vascularized tumors and extensive debulking can lead to significant blood loss.40 The large incision combined with surgery duration of up to 10 hours can cause large evaporative losses. Blood loss during these procedures can range from 0.5 to several liters.30,49 Additionally, peritoneal inflammation that begins during HIPEC continues postoperatively, leading to significant third-space fluid losses of up to 5 L per day.30 Replacement of these fluid losses is achieved through a combination of albumin and crystalloid solutions. Transfusion of fresh frozen plasma is guided by coagulation studies, and transfusion of packed red blood cells is guided by clinical signs and laboratory data suggesting inadequate oxygen delivery. Although studies of optimal replacement fluids in CRS and HIPEC are lacking, a recent meta-analysis of studies of patients with chronic liver disease and ascites found that replacement of ascites with albumin, compared with other intravascular volume expanders, reduced morbidity, mortality, and the incidence of circulatory dysfunction in this population.65 Although numerous studies have been reported on renal protective strategies, maintenance of adequate intravascular volume and renal perfusion may be the best method of preventing acute kidney injury.66,67
At our institution, we use pulse pressure variation, urine output, and point-of-care blood gas chemistries—lactate, base excess, and hemoglobin levels—to guide fluid administration. Although there are no specific guidelines regarding frequency of blood sampling during this procedure, optimal frequency of point-of-care testing depends on the carrier solution of the chemoperfusate and other patient-specific factors. During chemoperfusion, we check blood chemistries as often as every 15 minutes. In the case of hyperglycemia requiring an insulin infusion, we check point-of-care blood chemistries at least hourly.
Anticipated Physiologic Changes After HIPEC, patients are oftentimes admitted to the intensive care unit or remain in the postanesthesia care unit for monitoring of organ function, management of intraoperative complications, and correction of coagulopathy. Regardless of the location, they should be monitored with continuous telemetry and pulse oximetry. Physiologic perturbations during the perioperative period affect the duration of the patient’s stay in the intensive care unit and may precipitate multisystem organ failure. Similar to patients with other intraabdominal surgical procedures, these patients are at risk for bowel perforations, anastomotic leakage, bile leakage, fistula formation, pancreatitis, postoperative bleeding, wound dehiscence, deep vein thrombosis, and pulmonary embolism.21 In fact, the most frequently used drug in HIPEC for pseudomyxoma, mitomycin C, is not only associated with transient postoperative leukopenia and elevated transaminases, but also affects wound healing and results in an increased incidence in anastomotic leaks, especially in patients treated preoperatively with radiation therapy.68
Vasodilation often occurs after HIPEC. Management of the resulting hypotension focuses on expanding the IV volume, administering a vasoconstricting drug such as norepinephrine or vasopressin, and determining the underlying cause of vasodilation to target. Aggressive fluid resuscitation without assessment of fluid responsiveness should be avoided. Administration of excessive intravascular fluid to a nonfluid-responsive patient increases cardiac filling pressures, which in turn can cause pulmonary edema. Ultimately, the length of intensive monitoring will, in large part, be determined by the normalization of electrolyte and hemodynamic abnormalities.
Prevention of postoperative thromboembolic complications is of utmost importance because of the patient’s underlying high risk. Any standard perioperative regimen for prevention of deep venous thrombosis prophylaxis is recommended. Sequential compression devices are placed in the operating room and are continued postoperatively until patients start mobilizing.
Postoperative ileus is a common problem after CRS and HIPEC. Although there are no prospective studies evaluating the ideal postoperative nutrition strategies, a retrospective study by Arakelian et al.69 found that most patients were able to tolerate oral feeding between 7 and 11 days after surgery. To promote healing and improve intestinal transit, early enteral feeding is both safe and beneficial for these patients.70–72 Use of epidural anesthesia has been recommended by some as a strategy to reduce postoperative ileus.69
Pain Management Pain management for CRS and HIPEC is essential for patient comfort and postoperative pulmonary function optimization. Several centers use thoracic epidurals preoperatively for intraoperative and postoperative pain management.73 Other options include spinal morphine and IV opioid-based patient-controlled analgesia. No studies have been done comparing these different modalities. Epidurals can decrease postoperative IV opioid consumption and enhance bowel motility via decreased sympathetic tone. Additionally, adequate analgesia enables these patients to partake in early physical therapy and breathing exercises that aim to prevent postoperative atelectasis and pneumonia. Schmidt et al.40 performed a retrospective analysis of 78 patients treated with CRS and HIPEC in which 72% of patients in the cohort received a thoracic epidural. The researchers found that these patients received less intraoperative opioids and had a decreased period of postoperative intubation. Although no complications were reported from epidural placement, anesthesiologists should evaluate the patient’s platelet count, prothrombin time, and activated partial thromboplastin time before removing the epidural catheter according to the American Society of Regional Anesthesia guidelines.74
Outcomes and Morbidity and Mortality After CRS and HIPEC
Verwaal et al.75 showed that patients with peritoneal carcinomatosis secondary to colorectal cancer treated with CRS and HIPEC had a significant increase in median survival of 22 months compared with those treated with systemic chemotherapy alone (12 months). Peritoneal carcinomatosis secondary to ovarian cancer is unique in that current management combines CRS with systemic chemotherapy depending on the state at diagnosis.76 In a small prospective study, Spiliotis et al.77 showed that patients with peritoneal carcinomatosis secondary to ovarian cancer treated with CRS and HIPEC followed by systemic therapy demonstrated a significant increase in median survival of 19.5 months and a 3-year survival of 50% compared with patients treated with only CRS and systemic chemotherapy whereby median survival was 11.2 months and 3-year survival was 18%.
A systematic review of patients with pseudomyxoma peritonei treated with CRS and HIPEC demonstrated a median survival ranging from 51 to 156 months with 5-year survival rates ranging from 52% to 96% depending on severity of disease at time of treatment.78,79
In a systematic review involving more than 400 patients by Yan et al.,13 patients with primary peritoneal tumors secondary to diffuse malignant peritoneal mesothelioma treated with CRS and HIPEC demonstrated an overall survival rate of 53 months and a 5-year survival rate of 47%. Currently, CRS and HIPEC are recognized as the standard of care for managing peritoneal carcinomatosis secondary to colorectal cancer and appendiceal neoplasms.80
Given the extensive nature of CRS and HIPEC, it is not surprising that these treatments are associated with significant morbidity and mortality. Risk factors for major morbidity include peritoneal cancer index >21, ASA physical status >III, operation duration of >10 hours, left upper quadrant peritonectomy procedure, colostomy, ileostomy, and transfusion >6 U.81 With an improvement in surgical and perfusion techniques, morbidity and mortality associated with CRS and HIPEC have decreased. Sugarbaker et al.82 prospectively analyzed 350 patients with pseudomyxoma peritonei treated from 1998 to 2004 with CRS and HIPEC with mitomycin C in a single center experienced with peritoneal carcinomatosis. This group demonstrated a decrease in 30-day in-hospital morbidity and mortality from 35% and 5% to as low as 19% and 2%, respectively. It should be noted that these numbers are center-specific and depended not only on surgical volume but also physician and nursing staff expertise in caring for these patients. Data from other centers suggest a morbidity of 27% to 65% and mortality of 0% to 9%.83
Quality of life after CRS and HIPEC is also an important consideration during patient selection. Studies analyzing quality of life in long-term survivors have illustrated that functional status and pain scores return to baseline 4 to 6 months after surgery with quality of life returning to baseline levels 12 to 24 months after surgery.83–85
Safety Considerations for Operating Room Staff
There are 3 main mechanisms through which intraperitoneal chemoperfusion is accomplished: open abdominal technique, closed abdominal technique, and peritoneal cavity expander technique. Unlike the open and peritoneal cavity expander techniques, only the closed abdominal technique greatly decreases exposure and inhalation of the chemotherapeutic drugs.86–89 Stuart et al.88 analyzed the exposure of the surgeon and perfusionist during an open abdominal, intraperitoneal chemoperfusion of mitomycin C during 10 different cases. Although this was a small, underpowered study, they were unable to detect any significant safety hazard to operating room personnel with maximal exposure to antineoplastic drugs as evidenced by the lack of any detectable mitomycin C in air and urine samples. Additionally, powder-free, latex gloves proved to be a sufficient barrier against skin contact and/or absorption.88 This study also used a smoke evacuation device that was placed in the surgical field to remove any droplets or chemotherapy-contaminated air immediately surrounding the open abdomen.88 Mitomycin C was detected within the filter device but was below the Occupational Safety and Health Administration maximum allowable exposure during an 8-hour period.88 Of note, although not part of the Occupational Safety and Health Administration guidelines, some centers prohibit pregnant women, women trying to become pregnant, women with a history of miscarriages, people with a history of oncologic and immunosuppressant therapy, and those with a hematologic disease from partaking in the intraoperative management of patients undergoing hyperthermic intraperitoneal chemotherapy.86–89
Knowledge Gap and Future Direction
Designing clinical studies is very challenging in this patient population. Currently, there is no consensus among treatment centers regarding patient selection, optimal duration of HIPEC, perfusate temperature, and choice of cytotoxic drug. Creating a single system has also proven to be a formidable challenge. There are multiple staging systems, which vary in complexity and reproducibility. Thus, depending on the staging system used, a patient may have different degrees of tumor burden. Another challenge, in terms of defining outcomes, is the lack of clearly defined criteria of morbidity. Some centers routinely use the National Cancer Center Institute common toxicity criteria/grading system. Other centers include all postoperative complications, even those not specific to this procedure, when reporting morbidity from CRS and HIPEC. Having a single grading system would allow for the comparison of morbidity rates among centers. Additionally, centers that routinely incorporate adjuvant systemic chemotherapy or even postoperative intraperitoneal chemotherapy will also have differing morbidity rates. Another problem with designing clinical studies for this type of procedure is that standard IV chemotherapy regimens do not exist for all of the cancers that are under peritoneal surface malignancies. This paradigm exists for clinical studies involving isolated peritoneal carcinomatosis. Perhaps the most difficult factors to control for are tumor doubling time and aggressiveness of the cancer cells, both of which greatly affect outcomes. As we move forward, there are many questions that remain to be answered. Is there a role for perioperative chemotherapy, combining systemic and intraperitoneal chemotherapy? Is there a combination of chemotherapeutic drugs that maximizes tumor killing?
Optimal anesthetic management of patients being treated with CRS and HIPEC requires control of a complex interplay of physiologic mechanisms, including hyperthermia, abdominal hypertension, electrolyte abnormalities, coagulopathies, increased cardiac index, oxygen consumption, and decreased systemic vascular resistance.
Use of CRS and HIPEC presents a challenge to anesthesiologists. As this surgery continues to gain popularity among oncologic surgeons, further studies that clearly define the chemistry, pharmacokinetics, pharmacodynamics, and end points of efficacy need to be performed to elucidate optimal perioperative management.
Name: Christopher Allen-John Webb, MD.
Contribution: This author helped write the manuscript.
Attestation: Christopher Allen-John Webb approved the final manuscript.
Name: Paul David Weyker, MD.
Contribution: This author helped write the manuscript.
Attestation: Paul David Weyker approved the final manuscript.
Name: Vivek K. Moitra, MD.
Contribution: This author helped write the manuscript.
Attestation: Vivek K. Moitra approved the final manuscript.
Name: Richard K. Raker, MD.
Contribution: This author helped write the manuscript.
Attestation: Richard K. Raker approved the final manuscript.
This manuscript was handled by: Steven L. Shafer, MD.
We thank Joshua Leinwand and Robert Taub, MD, PhD, in the Division of Hematology/Oncology at Columbia University College of Physicians & Surgeons; John Chabot, MD, from the Department of Surgery and Sharyn Lewin, MD, from the Department of Obstetrics & Gynecology, Division of Gynecologic Oncology at Columbia University College of Physicians & Surgeons; and Charles Emala, MS, MD, from the Department of Anesthesiology at Columbia University College of Physicians & Surgeons, for reviewing the manuscript.
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