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REVIEW ARTICLE
Year : 2023 | Volume
: 24
| Issue : 1 | Page : 11-20
Perioperative hemodynamic management in surgery for phaeochromocytoma: A narrative review
Bhavya Krishna, Deepa Kerketta Khurana, Santvana Kohli, Kavita Rani Sharma, Ranju Gandhi
Department of Anesthesia and Intensive Care, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India
Correspondence Address:
Bhavya Krishna
D-52, Ground Floor, Saket, New Delhi - 110 017
India
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/TheIAForum.TheIAForum_32_23
Pheochromocytomas are rare adrenal tumors that produce excessive catecholamines and their surgical removal poses significant risks of intraoperative hemodynamic instability (HI) due to catecholamine release. This review article discusses the perioperative factors that impact hemodynamic lability and its management in patients undergoing surgical removal. A literature review was conducted by searching the electronic databases - Ovid MEDLINE, Embase, and Cochrane Library using appropriate Medical Subject Heading terms and keywords such as phaeochromocytoma, HI, and perioperative hemodynamic monitoring. The advancements in surgical and anesthetic techniques and appropriate preoperative medical optimization have contributed to a significant decrease in mortality rates. However, perioperative HI remains the biggest surgical and anesthetic challenge in treating pheochromocytomas. Patients with larger and more hormonally active tumors are at higher risk for extreme hypertensive episodes during surgery. Preoperative α-blockade, higher phenoxybenzamine doses, and laparoscopic approach improve the outcomes in phaeochromocytoma removal. Anesthetic techniques and drugs used during surgery may help prevent HI, but careful intraoperative management is essential. Perioperative HI can lead to increased surgical blood loss, patient morbidity, and prolonged intensive care unit (ICU) and hospital stay. Therefore, a multidisciplinary approach involving the surgeon, anesthesiologist, and ICU team is essential to ensure optimal perioperative management of patients with pheochromocytoma. Intensive hemodynamic monitoring may be required in the postoperative period to manage hypotension seen after tumor removal. In conclusion, perioperative HI is a significant risk during the surgical removal of pheochromocytomas, even with preoperative pharmacological treatment. Therefore, the use of appropriate preoperative medical optimization, surgical and anesthetic techniques, and careful intraoperative management can significantly improve the outcomes.
Keywords: Catecholamines, hemodynamic instability, hemodynamic monitoring, perioperative, pheochromocytoma
Pheochromocytomas are tumors that originate from chromaffin cells in the adrenal medulla, which produce, store, metabolize, and secrete catecholamines. Surgical removal of phaeochromocytoma under general anesthesia is the only curative therapy available, but it poses a significant risk of inducing a massive release of catecholamines into circulation during the procedure like during intubation, creation of pneumoperitoneum, and manipulation of the adrenal gland leading to hypertensive crises whereas resection of the tumor causes acute withdrawal of catecholamines resulting in hypotension and shock.[1]
Preoperative pharmacological treatment is assumed to lower the risk of intraoperative hemodynamic instability (HI), despite adequate pretreatment, intraoperative hemodynamic fluctuations can still occur. A widely acknowledged fact is that patients with larger and more hormonally active pheochromocytomas have more likelihood of experiencing more severe hypertensive episodes while undergoing surgery.[2]
Advancements in surgical and anesthetic techniques, appropriate preoperative medical optimization, and new imaging techniques for accurate preoperative tumor localization have contributed to a significant decrease in mortality rates, ranging from 0% to 2.9%.[3]
Even after all this progress, perioperative HI remains the biggest surgical and anesthetic challenge in treating pheochromocytomas. In addition to causing increased surgical blood loss, perioperative HI can result in serious adverse events, increased patient morbidity, and prolonged intensive care unit (ICU) and hospital stay. HI can be related to the rate (tachycardias and bradycardias), rhythm (tachyarrhythmias and bradyarrhythmias), and/or blood pressure (BP) (hypertension and hypotension).[4] Therefore, this review article aims to discuss preoperative, intraoperative, and postoperative factors that may impact perioperative HI and its management in a patient undergoing surgery for pheochromocytoma.
MethodologyA literature review was conducted by searching the electronic databases-Ovid MEDLINE, Embase, and Cochrane Library using appropriate Medical Subject Heading terms and keywords such as pheochromocytoma, HI, and perioperative hemodynamic monitoring. Advanced search using “phaeochromocytoma” AND “haemodynamic monitoring” as well as “phaeochromocytoma” AND “perioperative” AND “haemodynamic” resulted in a total of 439 articles. Articles specific to humans, written in English were included in this narrative review. The referencing manager used was Endnote, and after the removal of duplicates and including only literature from the last 15 years, a total of 303 references were shortlisted. These articles were reviewed by two authors individually to select the studies related to this narrative review.
We restricted this narrative review to perioperative hemodynamic monitoring and management of HI in patients undergoing surgery for the removal of pheochromocytoma.
Hemodynamic Instability and Its ManagementPheochromocytoma usually presents with the symptoms of sustained or paroxysmal hypertension and may also be associated with other features of catecholamine excess such as tachyarrhythmias and hyperglycemia. Most of the life-threatening cardiovascular manifestations of phaeochromocytoma, such as hypertensive emergencies, result from a rapid and massive release of catecholamines from the tumor. More rarely, patients with pheochromocytoma present with hypotension or even shock that may then precede a multisystem crisis. Reversible dilated or hypertrophic cardiomyopathy is well-established cardiac manifestations, with recent attention to an increasing number of cases with Takotsubo cardiomyopathy.[5]
The main challenge in the treatment of pheochromocytoma continues to be perioperative HI, which is characterized by arrhythmias, paroxysmal spikes in BP during tumor manipulation, and abrupt reductions in BP after tumor removal.[6] After reviewing various studies, we found no consensus definition of intraoperative HI. Various authors have defined HI using different variables, as elaborated in [Table 1]. A sudden and critical elevation in BP necessitating treatment characterizes a hypertensive crisis with systolic BP (SBP) >180 mm Hg or diastolic BP (DBP) >120 mm Hg with or without acute end-organ damage.[12]
Table 1: Definition of intraoperative hemodynamic instability in patients undergoing surgical removal of pheochromocytoma, as per various authorsSeveral steps during surgery may cause a surge in BP. These include a sudden change in the patient's position on the operating table; laryngoscopy and endotracheal intubation; intra-abdominal pressure changes (associated with cough, initiation of mechanical ventilation, a light plane of anesthesia, and insufficient relaxation or creation of pneumoperitoneum) or direct tumor manipulation.[13] Literature shows the varying incidences of HI observed ranging from 15% to 81%, with decreasing trend with adequate preoperative preparation.[3],[14],[15],[16]
Preoperative PreparationPreoperative preparation starts with the identification of modifiable and nonmodifiable risk factors influencing intraoperative hemodynamic control and addressing the preventable/modifiable risk factors.
Risk factors for hemodynamic instability
Tumor size, catecholamine secretion, hypertension history, and high urinary norepinephrine/epinephrine levels increase HI risk.[6],[17] Large tumor diameter, diabetes, and preoperative SBP fluctuation predict intraoperative HI.[14],[18],[19] Age, preoperative BP, body mass index (BMI), α-blockade duration/type, and procedure type also increase HI risk.[2],[20],[21],[22] Nonselective drugs lower hypertensive peaks but increase hypotensive phases.[10] Preoperative β-blocker therapy is an independent risk factor for postoperative hypotension.[17],[23]
Nomograms help identify factors to improve perioperative management, reducing morbidity/mortality.[24] Zhang et al. developed a tool for predicting intraoperative HI during adrenalectomy using several preoperative factors (age, tumor shape, etc.)[25] Bai et al.'s nomogram predicted intraoperative HI using BMI, presence of ischemic heart disease, tumor size, and preoperative volume expansion.[26] These user-friendly tools can aid clinicians in managing patients during surgery and potentially improve outcomes.
Preoperative optimization
The main goals of preoperative preparation of a patient scheduled for surgical resection are arterial pressure control, reversal of chronic circulating volume depletion, heart rate (HR) and arrhythmia control, blood sugar control, and assessment and optimization of myocardial function.[9] This involves both drug and fluid therapy tailor-made as per the symptomatology and physiology of each patient.
Drugs
To avoid unopposed alpha receptor-mediated vasoconstriction caused by catecholamine release and to address volume depletion, it is advised to prioritize alpha over β adrenergic blockade during preoperative medical preparation.[27] Despite recent skepticism, preoperative α-blockade remains a standard practice that aims to control arterial pressure before surgery, followed by the restoration of blood volume that can be adjusted using serial hematocrit measurements. Phenoxybenzamine and doxazosin remain the commonly used α-blockers for this purpose.[28] Initiation of α-blockade therapy preoperatively followed by volume expansion and β-blockade results in a massive decrease in perioperative mortality rate during pheochromocytoma surgery.[11] Many other short-acting vasoactive drugs have also been used in certain special circumstances.[8],[29]
[Table 2] highlights the drugs commonly used for arterial pressure control preoperatively.
Table 2: Drugs used for preoperative hypertension control in patients with pheochromocytomaAlpha-1 (α1) adrenergic blocker therapy, alone or in combination with beta blockers, calcium antagonists, and plasma volume expansion, is the most commonly used preoperative treatment protocol,[30] though α-blocker duration in days was a predictor for intraoperative HI.[14],[17] In 2020, a meta-analysis showed that peak SBP, DBP, and HR during adrenalectomy for phaeochromocytoma were not different in patients with and without α-blocker preparation.[31] Phenoxybenzamine should be stopped 24–48 h before surgery due to its long half-life, which may lead to postoperative refractory hypotension.[9] A study comparing calcium-channel blockers amlodipine with α-blocker prazosin for managing hypertension during phaeochromocytoma surgery showed amlodipine to be more effective than prazosin in keeping BP within the target range. Amlodipine may be a useful alternative for preventing HI during surgery.[32]
The Roizen criteria are used to recognize optimized patients with hypertension before surgery. The criteria include: BP below 160/90 mmHg for 24 h before surgery, no orthostatic hypotension with BP below 80/45 mmHg, no ST or T-wave changes for 1 week before surgery, and no more than 5 premature ventricular contractions per minute. Poorer outcomes have been observed when these criteria are not met before phaeochromocytoma resection surgery.[9]
PRESCRIPT trial suggests α-blockers before pheochromocytoma surgery to avoid instability and recommends that phenoxybenzamine is better than doxazosin in preventing intraoperative HI.[32] A meta-analysis on 1344 patients comparing selective versus nonselective alpha-blockers preoperatively determined no significant difference in morbidity between the two groups.[33] Varying preoperative preparation and intraoperative management differences affected hemodynamics but not outcomes in laparoscopic adrenalectomy.[34]
Preoperative initiation of terazosin combined with valsartan has been shown to effectively improve perioperative HI and reduce postoperative complications.[35] There are no clinically relevant differences between patients with phaeochromocytoma, who have been prepared for adrenalectomy with doxazosin or phenoxybenzamine.[36] A study by Kong et al. indicated that preoperative management of phaeochromocytoma with single α-receptor blocker doxazosin for more than 30 days after final dose adjustment might lead to intraoperative bradycardia and more postoperative hypotension requiring vasopressor support.[37]
Multiagent antihypertensive therapy with alpha adrenergic blocker and a combination of other antihypertensive medication should be given early although intraoperative HI is common despite adequate preoperative medical treatment. To date, there are no conclusive randomized controlled trials comparing the efficacy of the various preoperative optimization techniques and there is no universally accepted method of preoperative BP control.[38]
Preoperative fluid therapy
The recommended treatment for pheochromocytoma includes a high-sodium diet and fluid intake to restore blood volume before surgery.[7] This approach aims to reverse catecholamine-induced blood volume contraction.[9] Preoperative intravenous rehydration has been found to be ineffective in optimizing perioperative hemodynamics or improving early outcomes as per some authors.[37] However, restoring blood volume before surgery can reduce the risk of protracted hypotension or shock resulting from sudden vasodilation during surgery, according to some authors.[39] The absence of preoperative volume expansion can be an effective predictor of HI involvement, and guidelines recommend liberal preoperative volume administration.[25]
The catecholamines cause intense vasoconstriction through the α-1 receptors, and initiation of α-1 blocker therapy can lead to severe orthostatic hypotension. To overcome this, patients are advised to take 2–3 liters of fluid, or more if acceptable, orally with 5–10 g of salt to increase the intravascular volume. If oral fluid and salt intake do not improve orthostatic hypotension, and the patient's BP still warrants antihypertensive therapy, intravenous crystalloids and colloids may be given. Serial hematocrit measurements can guide the effectiveness of volume expansion, as a 5%–10% fall in hematocrit is typically seen in well-prepared patients. However, the fall in hematocrit is more of a guide to therapy rather than an endpoint for adequate volume expansion.[40]
Intraoperative ManagementHypertensive crisis and tachycardia during tumor manipulation and severe hypotension after vessel interruption are the most frequently described intraoperative complications.[2] In particular, the perioperative strategy should focus on three fundamental aspects: (a) treatment of hypertension and arrhythmias, (b) restoration of intravascular volume, and (c) treatment of any medical problem associated with excess catecholamines.[41] There are three critical intraoperative moments during adrenalectomy for pheochromocytoma: laryngoscopy and tracheal intubation, tumor dissection, and postligation of the main adrenal vein. Tauzin-Fin et al. showed that hypertensive episodes occurred primarily during insufflation to create pneumoperitoneum, manipulation of tumor inytraoperatively, and hypotension mostly occurred after tumor resection.[42]
Type of anesthesia
Anesthetic management during the surgical resection of pheochromocytomas is challenging due to potential hemodynamic fluctuations and/or postoperative complications. The chosen anesthetic technique should avoid drug-induced catecholamine release, catecholamine release induced by anesthetic or surgical maneuvers, minimize hemodynamic responses to tumor handling and treat episodes of hypotension, particularly after tumor devascularization.[9],[43] Despite the widespread use of combined epidural-general anesthesia, there is no agreement on whether this method is more effective than using general anesthesia alone. The primary objective is to maintain a deep level of anesthesia to suppress the cardiovascular system's reactions to catecholamine release.[44] The type of anesthesia was independently associated with the incidence of intraoperative HI. Total intravenous anesthesia increased the risk of intraoperative hypertensive events compared with balanced anesthesia.[45]
Drugs causing histamine release should be avoided as histamine can cause the release of catecholamines from chromaffin granules. Anxiolytic premedication drugs should be administered to patients to minimize stress stimuli.[46] Drugs such as pethidine, morphine, ketamine, droperidol, atracurium, pancuronium, ephedrine, metoclopramide, desflurane, and cocaine may increase catecholamine levels by inhibiting their reuptake, increase levels by promoting their presynaptic release, or increased catecholamines because of histamine release. Succinylcholine may theoretically provoke tumor catecholamine release by increasing the abdominal pressure from muscle fasciculation.[30]
It is recommended to avoid locoregional anesthesia as it can lead to increased sensitivity of the blocked areas to catecholamines.[46] The use of combined epidural-general anesthesia has been proposed as an independent factor for predicting both intraoperative and postoperative hypotension.[47] Epidural anesthesia alone is also an independent risk factor for both intraoperative and postoperative hypotension in patients undergoing surgery for the removal of pheochromocytoma with the incidence of hypotension in patients with and without epidural anesthesia being 88.7% and 58.8%, respectively.[48]
Goals of anesthetic management are outlined in [Table 3].
Surgery type
The surgical approach impacts HI in phaeochromocytoma patients.[4],[49] Open procedures have higher hypotension risk and need for vasopressors than minimally invasive laparoscopic approaches.[50] Retroperitoneal adrenalectomy may carry a greater risk than intraperitoneal, but posterior retroperitoneal adrenalectomy may have favorable outcomes.[15],[51] Robotic-assisted adrenalectomy may also achieve better outcomes. However, minimally invasive laparoscopic access is the gold standard for treating adrenal tumors, including pheochromocytomas.[15],[20],[52]
Monitoring
Invasive arterial BP monitoring and central venous catheterization are crucial for beat-to-beat BP monitoring and administration of vasoactive drugs, while higher-risk patients may benefit from Swan-Ganz catheterization for cardiac output and mixed venous oxygen saturation measurement. Intraoperative trans-esophageal echocardiography and esophageal Doppler may help visualize intraoperative changes in hemodynamics and avoid complications. Goal-directed fluid therapy should remain the standard of care.[53]
Hypertension
Surgical resection for pheochromocytoma has a high risk of hypertensive crises due to massive catecholamine release. Hypertensive crises occur in 51%–85% of surgeries and occur mainly during tumor manipulation. SBP >200 mmHg for >1 min requires treatment using drugs such as nitroglycerin, nicardipine, phentolamine, or magnesium sulfate.[28],[29],[54] Careful surgical handling, ligation of the main adrenal vein, and limited intra-abdominal pressure can limit hypertensive responses.[28] Undetected pheochromocytoma or unprepared patients may cause hypertensive crises with 80% mortality. Drugs that can be used for intraoperative hypertensive emergencies and arrhythmias are elaborated in [Table 4]. Institutional protocols for managing HI are significant in influencing intraoperative hemodynamics and should be standardized to minimize its incidence.[15]
Arrhythmias
Pheochromocytoma can cause various dysrhythmias, in around 20% of cases, due to excessive amounts of catecholamine release. The common dysrhythmias reported in the literature are sinus tachycardia (most common), supraventricular, ventricular and broad complex tachycardias, nodal rhythms, Wolff-Parkinson-White syndrome, atrial and ventricular fibrillation, torsade de pointes, and asystole. Reflex bradycardia, atrioventricular (AV) dissociation, bigeminy, right bundle branch block, sick sinus syndrome, and nodal escape rhythms have also been reported during and between hypertensive emergencies, possibly due to reflex increased vagal tone. Sinus tachycardia is the most common arrhythmia seen.[5] Epinephrine or norepinephrine release during tumor manipulation can also lead to bradycardia with hypertension or tachyarrhythmia.[46] Hemodynamic changes and bradyarrhythmias, sympathovagal responses, including second-degree type I AV block, can occur during tumor handling.[55] Management involves continuous electrocardiography (ECG) and BP monitoring, communication between surgical and anesthesia teams, gentle handling of the tumor, correction of electrolyte and acid − base anomalies, and the use of appropriate antihypertensive and antiarrhythmic agents. No ECG finding is pathognomonic to phaeochromocytoma, so other causes must be ruled out.
Fluids
The usefulness of preoperative intravenous fluid administration in adrenalectomy for pheochromocytoma is debated, with some studies suggesting no improvement in outcomes and a lack of evidence-based support. However, other studies recommend preoperative volume expansion to minimize severe hypotension after surgery. Lentschener et al. found that only intraoperative fluid transfusion was required, especially when BP dropped during surgery and reported no deaths related to HI.[28] Meanwhile, Lenders et al. recommend preoperative volume expansion to prevent hypotension and related complications in their clinical practice for pheochromocytoma.[56] Vasoplegia, but not hypovolemia, was observed after tumor resection, indicating no benefit of liberal fluid administration during laparoscopic adrenalectomy in pheochromocytoma patients. Hence, while dehydration can lead to severe hypotension after tumor resection, overhydration can lead to pulmonary edema and congestive heart failure in an already compromised heart.
Hypotension
During surgery, hypotension can result from factors such as hypovolemia, α-blockade, and sudden catecholamine deficiency. Severe intraoperative hypotension can lead to complications such as acute kidney injury, stroke, or myocardial infarction.[6] According to several studies, nearly all patients encounter hypotension, while hypertension occurs in only a third of the patients, particularly when they are adequately prepared preoperatively. In particular, patients with more than five episodes of severe hypotension require more perioperative fluid administration and have a significantly longer ICU and hospital stay, while patients experiencing severe hypertensive episodes had no long-term impact.[4] The incidence of intraoperative HI episodes (both SBP ≥160 mmHg and mean arterial pressure <60 mmHg) remained independent predictors for postoperative all-cause morbidity.[18]
Phenylephrine is commonly used, but other options such as norepinephrine, epinephrine, and vasopressin should also be considered.[51] Vasopressin can be effective in cases of refractory hypotension. Case reports show successful use of vasopressin, with bolus dose administration followed by an infusion that can be frequently weaned over 2–12 h.[57],[58] Agents which may be used to treat intraoperative hypotension are enlisted in [Table 5]. It may however be noted that fluid and blood replacement remains a priority to keep central venous pressure and hematocrit within acceptable levels, respectively.[46],[54]
Postresection hypotension
In the early period following tumor removal, many patients require vasopressor agents due to various factors. Hypotension is a common occurrence, which is variably reported to have an incidence of 20%–70% and may be influenced by preoperative α-antagonist use and intraoperative antihypertensive therapy.[4],[50] Effective communication between surgical and anesthesia teams is vital, with treatment starting before adrenal vein ligation. Fluid loading and vasopressor infusion are required to counteract the hypotension, which is usually short-lived but can be refractory and prolonged in some cases. Preoperative β-blockade therapy has been identified as the only independent predictor of postoperative hypotension by Thompson et al.[59] Postoperative HI is associated with a down-regulation of α and β-adrenergic receptors caused by catecholamines. Tumor size and preoperative catecholamine levels are also linked to postoperative hypotension, with higher urine epinephrine levels and greater preoperative highest HR being predictive factors.[17],[58] Combined epidural-general anesthesia is a risk factor for postresection hypotension.[47] Patients who experience more than five episodes of severe hypotension require more perioperative fluid administration and have significantly longer stays in the ICU and hospital.[4]
Postoperative CareSurgical removal of pheochromocytoma is a major abdominal surgery, even though performed laparoscopically, it may require high-dependency unit or ICU care postoperatively. Oxygen supplementation, hemodynamic monitoring, blood sugar control, pain relief, and fluid management are the standards of care in the postoperative period. Vasoactive agents are usually tapered and stopped over the next few hours to days. An epidural catheter if inserted may be used for pain relief.
ConclusionPreoperative α-blockade improves the outcomes in pheochromocytoma removal. The laparoscopic approach and higher phenoxybenzamine doses also improve outcomes. Several anesthetic techniques and drugs used during surgery may help prevent HI. Preoperative lower phenoxybenzamine dose and vasopressin use predict HI. Minimally invasive surgery and careful intraoperative management are important. Intensive hemodynamic monitoring may be required in the postoperative period to manage hypotension.[60]
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