The results of this study indicate that the incidence of IVVD in the immediate pre-operative period in patients with PCC/PGL who have received optimized medical therapy with alpha blockers and oral fluid and salt replenishment is nearly 60%. The incidence is similar to patients with essential hypertension who have been subject to standard nil per oral guidelines prior to elective surgery.
Incidence of IVVD: Patients with functional PCC/PGL have a contracted blood volume. There is relative intravascular hypovolemia and this can become exaggerated after α-blockade due to vascular dilation, resulting in postural hypotension. Rehydration is, therefore, advised to the patients concurrent with the commencement of α-blockade to prevent severe hypotension. Patients feel thirsty and, hence, fluid intake is reflexively increased. The actual incidence of preoperative IVVD in patients undergoing various surgical procedure is reported contrarily in previous studies. Some have reported no intravascular volume depletion according to various definitions after standard overnight fasting guidelines [13, 14]. Some other authors do report incidence of IVVD similar to ours [11, 15] (Actual incidence of IVVD in these references is not clear as per our definition). In none of the previous studies, however, incidence of IVVD has been sought specifically in hypertensive patients. On the other hand, patients in our control group were also hypertensive patients on various hypertensive drugs. All pre-operative patients in our Institute are kept fasting for both solids and liquids for 8 hours unless otherwise specified. The fact that the incidence of IVVD was similar in our groups may indicate that the oral hydration therapy being prescribed to patients with PCC/PGL may be effective. The results also imply that incidence of IVVD is substantial despite considerable oral fluid and salt replenishment in patients undergoing surgical resection of PCC/PGL.
Association of IVVD with peri-operative morbidity: Studies including non-PCC/PGL patients have shown the association of pre-induction/pre-operative IVVD with increased incidence of post anesthesia induction hypotension [15, 16]. This was not observed in patients with PCC/PGL in our study. In our study group, only 2 patients with IVVD had post anesthesia induction hypotension. This could be attributed to the altered hemodynamic milieu and vascular status of these patients due both to pre-operative oral fluid and salt replenishment and increased tumor related catecholamine levels in the body. Post induction hypotension is undesirable in these patients as unlike other patients, use of sympathomimetic drugs before isolation of the tumor, to counteract post induction hypotension can be of concern in patients with PCC/PGL. Increased intravenous fluid infusion is also undesirable in these patients due to possibility of cardiomyopathy [9]. At our Institute active measures are taken to avoid post induction hypotension in these patients (slow and titrated infusion of propofol, and co-induction with etomidate and/or opioids). This could have also led to decreased incidence of post anesthesia induction hypotension.
Previously, many authors have mentioned that IVVD is associated with increased incidence of post operative vasopressor support in patients undergoing PCC/PGL removal [17–20]. Recent studies, have however, refuted this assumption. A recent meta-analysis which included nine studies with a collective number of 967 patients reported that peri-operative hemodynamic instability was only associated with tumor size and urinary norepinephrine levels [21]. Though they sought to evaluate peri-operative fluid with hemodynamic instability the data was insufficient to reach conclusion. All the studies included in this meta-analysis were retrospective. Many authors have found it to be a reasonable assumption that post tumor removal vasoplegia and the persistent effect of alpha and beta blockers play a more prominent role in need for vasopressor therapy rather than fluid depletion [10, 21–24]. An early initiation of vasopressor therapy is, thus, a more prudent choice of treatment rather than unguided massive fluid infusion.
Intravascular volume depletion can be a result of vasodilatation due to alpha-blockade therapy. This would probably lead to the conclusion that patients with IVVD will have a lesser number of hypertensive spikes intra-operatively as they are relatively more “alpha-blocked”. In the present study, however, patients with IVVD did not have lesser number of hypertensive spikes. Neither was IVVD associated with the total dosage of alpha-blocker drugs or number of anti-hypertensive drugs being received by the patient.
Various centers follow different fluid repletion regimens. In our institute, more emphasis is placed on voluntary oral fluid therapy along with salt repletion rather than IV fluid therapy. The patients are, however, instructed to take a minimum of 3–4 liters orally. Large amount of oral fluid intake may be unpleasant to patients. On the other hand, IV fluid therapy has its inherent associated risks of thrombophlebitis, infection and fluid extravasation. Many studies have now de-emphasized the need for compulsory IV/ oral fluid therapy as part of pre-operative optimization protocols [21, 23, 24].
Association of other perioperative parameters with morbidity: In our study, other perioperative variables were analyzed to predict the initiation of vasopressor in PCC and PGL patients. It was observed that presence of other comorbidities, amount of preoperative fluid intake, number of intraoperative hypertensive spikes, maximum tumor diameter, total dose of alpha and beta blocker drugs per day, and number of different antihypertensives used for preoperative optimization did not have any association with the initiation of vasopressors in the postoperative period.
Use of post-operative vasopressor was significantly associated with need for intra-operative vasodilator therapy. This again supports the assumption that persistent effect of anti-hypertensive therapy (used intra-operatively for control of hypertensive emergencies) might be a reason for post-operative hypotension.
The difference in demographic details of patients in both the groups is expected as patients in PCC and PGL present as secondary hypertension at an early age. Patients with PCC and PGL have low weight and BMI due to their high metabolic rate while it is a well-established fact that obesity is a risk factor for essential hypertension and this group of patients are expected to have a greater BMI [25].
Regarding IVC-CI as a measure of IVVD: Ultrasonographic assessment of IVC-CI is an established technique and gives an accurate dynamic measure of volume status even in spontaneously breathing patients [11]. It is a safe and easy to perform non-invasive method that can be easily performed on awake patients compared to the other dynamic parameters that are used for the assessment of intravascular status. Previous studies have analyzed intraoperative systolic pressure variation and transesophageal doppler to guide intraoperative fluid therapy but no comment has been made on how preoperative fluid intake has impacted their intravascular volume status [21, 22].
Strengths and Limitations: This is a prospectively done study and being a rare disease, it is difficult to do prospective study in this cohort. Due to the ongoing COVID-19 scenario, we had to curtail the sample size in Group P to thirty-two patients due to temporary suspension of elective surgeries during our study period. It has its inherent limitations of being a non-randomized and non-blinded study, as with-holding preoperative oral therapy may be construed as with-holding standard of care. The drug therapy in the control group was not standard and data related to use of diuretics which could have affected the pre-operative intravascular status of these patients could have been a confounding factor in measurements.