Case Reports in Anesthesia

Blog with interesting cases and/or problems related to anesthesia with discussion based on best evidence in the literature.

February 23, 2024

DIEP flaps at our institution

 I recently started a new position at a facility that performs a fair number of DIEP flaps after breast cancer surgery.  The surgeries are very adamant that the anesthesia provider avoid all vasopressors and give at minimum 4 to 5 liters of fluid regardless, and also use additional repaid fluid infusion to treat and prevent hypotension.  This approach is actually written down as instructions to the anesthesia providers on how to approach their patients.  In my previous practice we did flap repairs but never received direct instructions from the surgeons involved with an algorithm to treat hemodynamic perturbations.  Therefore, when I arrived here and received a "recipe" for the approach to treatment of hypotension, I was surprised.

The concept of "loading the patient with crystalloid" as indicated by our plastic surgeons derives from the idea in free flap physiology related to maintain low SVR in a relative sense with elevated cardiac output. It is clear that, when a patient is hypovolemic, the natural response in the healthy intact human is to see elevated levels of ANP and sympathetic nervouse system output resulting in vasoconstriction.  Therefore, the fear of a patient having a large sympathetic response with significant vasoconstriction and low cardiac output prompts the concept of giving large amounts of fluids to avoid this.  Unfortunately, this ignores the idea that in patients who are appropriately anesthetized, the baroreceptor response is blunted, and sympathetic response is severely mitigated.  Patients under GA find themselves in a state of low SVR although cardiac output is often not increased as desired by the free flap surgeon.  Unfortunately, large volume crystalloid may be harmful.  In an elegant review on the endothelial and endothelial glycocalyx physiology by Millford et al. [11], one can see how infusing large volumes of crystalloid may or may not remain in the intravascular space depending on the intrinsic intra capillary pressure.  As this pressure increases, any crystalloid infused will simply be "pressed" out of the intravascular space and into the interstitial space.  Here, excess fluid will then interefere with tissue oxygenation and thus degrade perfusion of the free flap intended to protect.  Furthermore, there is evidence that diluting albumin with large volume crystalloid intereferes with the endothelial glycocalyx integrity.  In theory this will allow a greater flux of fluid across the endothelial lining of capillaries resulting in greater interstitial fluid accumulation. In research that highlights this physiology, it has been shown that when healthy volunteers are hemorrhaged 900 mL, an equal amount to 2 x 's this volume of balanced crystalloid can restore normovolemia. This is an example of unique microcirculation physiology, where the intracapillary pressure is decreased by hemorrhage, thus allowing infusing crystalloid to remain in the intravascular space.  In comparison, when crystalloid in infused to induce hypervolemia, only 17% (+/-) 10% remains in the intravascular space, the rest being pushed (squeezed) into the interstitial space.  If the endothelial glycocalyx is damaged, the amount of crystalloid OR colloid infused will now be pushed into the interstitial space at lower pressures in the capillaries.  With severe endothelial glycocalyx degradation, both colloids and crystalloids will move out of the intravascular space into the interstitial space in equal volumes. The amount of fluid that is lost across the endothelial membrane is then largely a function of elevated pressure within the microvascular space AND intactness of the glycocalyx.  There is evidence to suggest that large volume crystalloid infusion can disrupt or cause breakdown of the glycocalyx. Furthermore, albumin  carries the phospholipid sphingosine 1 phosphate (S1P), which is essential in the maintenance of the endothelial glycocalyx structure. There is evidence that demonstrates that as the albumin concentration decreases thus interrupting S1P transport endothelial glycocalyx suffers significantly degradation. It has been demonstrated that in absence of albumin, 25 times less S1P is released from RBC's (its primary source). Furthermore, there is some evidence in animal models suggesting that albumin infusion can restore the glycocalyx.  However, it is clear that albumin is not likely to be able to restore  glycocalyx function directly, rather, it is the S1P that the albumin coaxes out of RBCs or the S1P in the albumin solution infused that mediates repair. On the other hand, FFP has clearly been demonstrated to be restorative to the glycocalyx structure via upregulation of endothelial glycocalyx component production.


   Thus, preserving endothelial glycocalyx structure is critical when caring patients undergoing DIEP flap (or any other free flap).  This goal is put at risk when we are asked to rapidly administer high volume crystalloid solutions (and in particular when the crystalloid consists of NS).  The damage done may be less when administering large amounts of crystalloid to patients who are hypotensive, at least while microvascular pressures remain low. However, there can be a reversal in the post operative period when baroreceptor function returns and microvascular pressures return to normal resulting in a relative hypervolemia in contradistinction to the relative HYPOvolemia produced by induction of anesthesia.

Above is a practical physiologic rationale for avoiding large volume crystalloid.  However, I wanted to see if there was good clinical evidence from real world studies that support avoidance of large volume crystalloid infusions. Karamanos et al. [1] performed a retrospective review of 126 patients undergoing DIEP flap. One group had received 5.5 mL/kg/hr vs liberal fluid group who had received 10.2 mL/kg/hr. The group who received liberal fluids (more fluid) had more wound complications (76% vs 15%). Furthermore, the flap oximetry  readings were lower in the liberal fluid group over the 24 hours following surgery (41% vs 56%). No difference in AKI between groups.  It is interesting to note that the flap oximetry readings were lower in the liberal fluid regimen group.  This is direct evidence of the extra fluid finding its way into the interstitial space thus harming tissue oxygen tissue levels. In another retrospective review on breast reconstruction surgery by Sjöberg, T et al. [2] a  moderate fluid therapy group was compared to liberal fluid therapy. It should be noted that radiotherapy was more frequent in the group that received the moderate fluid making them at higher risk for post op complications with wound healing. Neverthless, despite this, the study found that intraop and post op complications were more frequent in the liberal fluid group.  The moderate fluid therapy group included noriepi as part of the protocol to treat hypotension. Zhong T, et al. did a retrospective multivariate analysis and found that extremes of crystalloid infusions predicted post operative complications (p=0.03). This analysis carefully controlled for a multitude of different possible causes of post op complications.

On the other hand, if one follows the general theme outlined above, it is likely that low blood pressure may in some cases require intervention. Allowing lower MAP during a free flap has very likely negative impacts on flap perfusion which is highly sensitive to perfusion pressure given that local innervation is erradicated when the flap is removed from its native neurovascular bundle. On the other hand, free flap surgeons often consider all vasopressors to be contraindicated.  This concept is not supported by general hemodyanamic physioglogy however. In particular, in patients whose stressed volume has been shifted to the unstressed vasculature after induction of and during maintenance of anesthesia, small doses of phenylephrine has been shown to increase cardiac output by shifting blood from the unstressed compartment (i.e. venous reservoir) into the stressed compartment. To state in other words, in normovolemic patients whose cardiac output is depressed due to decreased venous return, phenylephrine will predominantly increase blood pressure by increasing cardiac output via increased preload.  This increase in cardiac output will improve perfusion pressure to organs who are flow dependent for perfusion of oxygen. It has been documented, that in normal physiology, venous vasculature has a larger number of alpha receptors than that located on arteries and arterioles. Obviously, improving venous return via alpha 1 agonism depends exquisitely on ensuring normovolemia in your patients. Nevertheless, basic clinical research suggests that in general anesthesiologists should use vasopressors as needed in this patient population based on a perusal of a number of studies. For example Motakef et al. [3] published a systematic review of literature where they found that there is a high level of evidence that fluid should be between 3.5 ml/kg/hr up to max of 6 mL/kg/hr. Vasopressor use do not harm outcomes and may improve flap flow (highest level of evidence).  Chen et al. [4] performed a retrospective review on 187 patients and found that vasopressor use not associated with any negative consequences of any type. Eltorai et al. [5] also found this.  In a retrospective review they showed that Ephedrine treatment for hypotension during DIEP flap cases is associated with decreased intraoperative flap complication rates compared with controls who did not receive vasopressors, whereas phenylephrine has no significant association.  In a systematic review of studies done in head and neck free flaps the authors [6] looked at the effect of using vasopressors for BP control to determine if this increased risk of complications.   The review included one prospective and nine retrospective studies. Authors concluded that administration of phenylephrine and/or ephedrine was not associated with any complications which included: free flap failures, pedicle thrombosis, or other flap complications.  In a prospective observational study in 169 ENT free flap surgeries Monroe et al.  concluded that vasopressor use does not increase the risk of pedicle loss or complications in this population [7].   In yet another review of 320 patients who received vasopressors (phenylephrine and ephedrine) during free flap surgery for head and neck Harris et al. [8] determined that the administration of vasopressors were not associated with any complications or increased failure rate of flaps. In a different surgical population a retrospective review of 110 jejunal flaps for pharyngeal tumors was completed. Chen et al. [9]  were able to show that when phenylephrine and ephedrine were used there was no increase risk of complications or flap failures.


Therefore, optimizing perfusion of free flaps shares the same physiological approach utilized everyday by anesthesiologists whose is to optimize perfusion of all organs.  While it is true that due to denervation of the free flap perfusion pressure may not be automatically controlled by intrinsic bodily physiology, anesthesia providers can easily overcome this obstacle as they do in other scenarios (i.e perfusion of placenta in obstetric anesthesia).  Evidence suggest strongly that maintaining normovolemia by judicious use of a balanced crystalloid solution with careful titration of vasopressors when needed is the best approach to free flap microsurgery anesthesia based on current evidence.




1.  Karamanos E, Walker R, Wang HT, Shah AR. Perioperative Fluid Resuscitation in Free Flap Breast Reconstruction: When Is Enough Enough? Plast Reconstr Surg Glob Open. 2020 Mar 28;8(3)


2. Sjöberg, Thomas MD*,†; Numan, Anmar MD†,‡; de Weerd, Louis MD, PhD*,†. Liberal versus Modified Intraoperative Fluid Management in Abdominal-flap Breast Reconstructions. A Clinical Study. Plastic and Reconstructive Surgery - Global Open 9(9):p e3830, September 2021. | DOI: 10.1097/GOX.0000000000003830


3. Motakef S, Mountziaris PM, Ismail IK, Agag RL, Patel A. Emerging paradigms in perioperative management for microsurgical free tissue transfer: review of the literature and evidence-based guidelines. Plast Reconstr Surg. 2015 Jan;135(1):290-299. doi: 10.1097/PRS.0000000000000839. PMID: 25539313.


4. Chen C, Nguyen MD, Bar-Meir E, Hess PA, Lin S, Tobias AM, Upton J 3rd, Lee BT. Effects of vasopressor administration on the outcomes of microsurgical breast reconstruction. Ann Plast Surg. 2010 Jul;65(1):28-31. doi: 10.1097/SAP.0b013e3181bda312. PMID: 20548236.

5. Szabo Eltorai A, Huang CC, Lu JT, Ogura A, Caterson SA, Orgill DP. Selective Intraoperative Vasopressor Use Is Not Associated with Increased Risk of DIEP Flap Complications. Plast Reconstr Surg. 2017 Jul;140(1):70e-77e. doi: 10.1097/PRS.0000000000003444. PMID: 28654605.



6. Naik AN, Freeman T, Li MM, Marshall S, Tamaki A, Ozer E, Agrawal A, Kang SY, Old MO, Seim NB. The Use of Vasopressor Agents in Free Tissue Transfer for Head and Neck Reconstruction: Current Trends and Review of the Literature. Front Pharmacol. 2020 Aug 28;11:1248. doi: 10.3389/fphar.2020.01248. PMID: 32982724; PMCID: PMC7485519.

7. Monroe, M.M., Cannady, S.B., Ghanem, T.A., Swide, C.E. and Wax, M.K., 2011. Safety of vasopressor use in head and neck microvascular reconstruction: a prospective observational study. Otolaryngology--Head and Neck Surgery144(6), pp.877-882.

8. Harris, L., Goldstein, D., Hofer, S. and Gilbert, R., 2012. Impact of vasopressors on outcomes in head and neck free tissue transfer. Microsurgery32(1), pp.15-19.

9. Chan, J.Y.W., Chow, V.L.Y. and Liu, L.H.L., 2013. Safety of intra‐operative vasopressor in free jejunal flap reconstruction. Microsurgery33(5), pp.358-361.

10. Swanson EW, Cheng HT, Susarla SM, Yalanis GC, Lough DM, Johnson O 3rd, Tufaro AP, Manson PN, Sacks JM. Intraoperative Use of Vasopressors Is Safe in Head and Neck Free Tissue Transfer. J Reconstr Microsurg. 2016 Feb;32(2):87-93. doi: 10.1055/s-0035-1563381. Epub 2015 Sep 4. PMID: 26340760.

11. Fang L, Liu J, Yu C, Hanasono MM, Zheng G, Yu P. Intraoperative Use of Vasopressors Does Not Increase the Risk of Free Flap Compromise and Failure in Cancer Patients. Ann Surg. 2018 Aug;268(2):379-384. doi: 12.1097/SLA.0000000000002295. PMID: 28489683.

13. Milford EM, Reade MC. Resuscitation Fluid Choices to Preserve the Endothelial Glycocalyx. Crit Care. 2019 Mar 9;23(1):77. doi: 10.1186/s13054-019-2369-x. PMID: 30850020; PMCID: PMC6408751.

June 28, 2023

complex robot VHR in patient with smoking induced COPD

 a 59 year old male presented with a complex VHR via robot laparoscopy.  He had a prior history of drug abuse, hepatitis C and a long smoking history resulting in mild undiagnosed and untreated COPD.  


The patient was given a GETA anesthetic with sevoflurane, rocuronium, dilaudid, and low dose ketamine. During the anesthetic, his minute ventilation was unusually large for this 71 kg male.  His peak airway pressures were also elevated despite no trendelenburg positioning requested from the surgeon.  The procedure began at approximately 7:45am and closure was completed just prior to 5:00pm.  Multiple ventilation manipulations were provided in an atttempt to improve ventilation, decrease airway pressures including driving pressure as well as minute ventilation.

In the October 2020 Journal Anesthesiology [1], An article on ventilation in obese patients undergoing laparoscopy surgery appeared.  This article discussed a new paradigm emerging in ventilatory medicine to improve ventilation while reducing the incidence of ventilator induced lung injury (VILI). Dozens of studies showed reduced mortality in ICU patients who were ventilated due to ARDS when they were treated with low plateau pressure (Pplat) which often required reducing tidal volumes (Vt) to around 6 to 8  mL/kg and permissive hypercapnia.  This has evolved over the years and there are now several studies indicating that the improvement in outcomes may be related more to reducing the driving pressure (Pdrive) rather than a purely low Vt permissive hypercapnea strategy.


It is noted that Transpulmonary pressure is the pressure felt by the lung tissue itself and therefore the main concern when attempting to limit or avoid VILI.  It has been identified that during robotic surgery in particular,  airway pressures generated when attempting to ventilate the patient are not similar to a patient who is undergoing non robotic surgery.  In particular, the airway pressure measured by the ventilator is diverted from the lungs to the chest wall.  This occurs because during robotic surgery, chest wall compliance can decrease by up to 300% while lung tissue compliance decreases by only 50%, and thus.   To restate, higher chest wall stiffness results in a lower fraction of airway pressure distributed to the lungs during the Trendelenburg position and docked robot condition than after intubation.  Measurements in  non obese patients, after docking and insufflation of the abdomen, found that the fractional pressure presented to the lungs by mechanical ventilation is reduced  (48% from 63% immediately after intubation). In the obese patient (BMI 30-40), the decrease is from 80% after intubation to 56% after docking.  In essence, because the chest wall compliance decreases dramatically after docking the robot, the lungs are now "protected" or shielded to a degree from high "airway pressures".  To illustrate, lets take an example patient with BMI  of 40 whose plateau pressures immediately after intubation are 27 cmH2O.  If 80% of this pressure is distributed to the lungs, they would be impacted by (0.8 x 27)= 21.6 cmH2O while the rest would be distributed to the chest wall.  Now, after docking, and pneumoperitoneum has been established the Plat increases from 27 cmH2O to 35 cmH2O.  If we now calculate the fractional pressure applied to the lungs we see that it is (0.56 x 35) = 19.6 cmH20. The other pressure is applied to the chest wall (35 cmH2O - 19.6 cmH2O)= 15.4 cmH2O.  Obviously, these numbers are explanatory only to make a point.  However, it is important to understand that this occurs due to the differential change in compliance of the chest wall (decreased by up to 300%) vs the decrease in compliance of the lungs (up to 50%). 

  Overzealous limitation of PEEP or tidal volume to maintain plateau pressures less than 28 to 30 cm H2O in such cases could expose patients to unnecessary hypoxemia, hypoventilation, and mechanical injury.  

After the benefits of lower tidal volumes and permissive hypercapnea were realized, a large number of studies attempting to translate these results into clinical anesthesia were published.  Unfortunately, the results were scattered with many studies unable to clearly show definite and meaningful benefits with "lung protective ventilation" strategies during routine clinical mechanical ventilation.  In general, patients were divided into groups of high vs. low Vt (i.e. 10-12 ml/kg vs. 6-8 ml/kg) and groups of standard PEEP or no PEEP.  The PEEP applied was usually standardized in the group that received PEEP anywhere from 2 up to 10 cmH20. Another recent trial found that PEEP of 12 cmH2O vs. 2 or less provided no benefit to patients undergoing open abdominal surgery.  While there was no improvement in post op pulmonary complications (PPCs), the high PEEP group experienced more hemodynamic instability and required more fluid.  This led many to recommend low PEEP.  However, Tharp et al. [1], showed that individualizing applied PEEP,  improves mechanical ventilation parameters.  Tharp et al found that in patients with normal BMI,  optimal PEEP was 9.7 cm H2O (+/- 3.7), whereas, for obese patients (BMI >= 40), optimal PEEP was 21.3 cmH2O (+/- 7.4). High PEEP has been shown beneficial in other studies of obese patients with ARDS, where PEEP as high as 20 cm H2O showed benefit[3].  The real takeaway from the Tharp paper [1], is the observed high variability in optimal PEEP between patients.

Post operative pulmonary complications and VILI can be understood by stress and strain placed on the alveoli. Excessive alveolar strain during ventilation may result in injury, and in predisposed patients will lead to post operative pulmonary complications (PPCs).  Strain to the alveoli can be quantified and understood via the equation Vt/FRC ratios.  Since the strain is equal to the ratio of change in volume to initial volume, understanding that if FRC drops in your patient as you anesthetize them, total alveolar strain will increase.  As example, if you have a two patients both with Vt of 500ml but different FRCs, they will experience large differences in total alveolar strain during ventilation.


Patient 1: Vt=500mL and FRC 2000mL strain = 25%

Patient 2: Vt=500mL and FRC 500mL (due to ARDS) strain = 100% (four fold increase)


Intraop, we can't directly measure strain, although this variable is obviously incredibly important in causing lung injury if elevated.  However, we can indirectly get clues as to the strain we are applying to the airways by measuring the driving pressure.  Simply, Driving pressure (Pdrive) is the plateau pressure (Pplat) minus PEEP. Pplat is measured at the end of an inspiratory pause during volume controlled ventilation.  The inspiratory pause is important as no flow can occur during measurement for accuracy.  Fortunately, all modern anesthesia ventilators can apply this after each breath in order to measure Pplat. As we learn more about our ability to measure ventilation parameters and how to change those parameters to improve outcomes, anesthesiologists will find greater roles in controlling outcomes.  Pdrive is a concept that is gaining greater traction.  Essentially, Pdrive is expressed as the ratio between Vt and respiratory system compliance (Crs).  Crs correlates closely with the aerated lung volume. Recent studies have demonstrated that Pdrive is a better indicator than purely Vt management to predict pulmonary outcomes. in 2015, a large analysis of patients with ARDS [4] was completed where it was shown that independent changes in Vt or PEEP were not independently associated with survival.  However, Pdrive was associated independently with survival EVEN in patients receiving protective Pplat and Vt.  In this study, the cut off point where risk was increased was Pdrive of 15 cmH2O.  One year after the above was published a large meta analysis was completed looking at studies using "protective ventilation" to reduce post operative pulmonary complications [5]. They included data from 17 RCT with 2250 patients. A multivariate analysis suggested that Pdrive was associated with PPCs (there was a 13% increased probability of PPCs for every 1 cmH2O increase in Pdrive). There was no association at all with Vt or PEEP. 

Unfortunately, Pdrive as a surrogate for acquiring measurement of transpulmonary pressure (what we are really after) can be unreliable in situations where Chest wall compliance is dramatically altered. This occurs as mentioned above during laparoscopy especially when robotic and in steep trendelenburg positioning. For example, increasing intraabdominal pressure increased Pplat by 50% of the applied intraabdominal pressure, but produced minimal change in transpulmonary pressure (Plung) in healthy lungs. In contrast, in the presence of lung injury, both Pdrive and Plung increased with increasing intra-abdominal pressure.  In obese patients undergoing robotic laparoscopic surgeries, adequate mechanical ventilation may be difficult. In these situations there is a push to use esophageal manometry to directly measure pleural pressure which allows a direct measurement of transpulmonary pressure. Unfortunately, esophageal manometry is unavailable in routine clinical anesthesia. Therefore, given the tools at our disposal, how does one determine the "ideal" PEEP so as to decrease Pdrive when it becomes a challenge. As made clear above, routine application of 5 cmH2O of PEEP is likely not what any given patient will need. Previous studies have shown that "ideal" PEEP in obese patients ranged from 13 to 25 cmH2O. Tharp found using individualized PEEP titration using esophageal manometry that not all obese patients require higher PEEP settings.  High PEEP can reduce venous return, right ventricular after load, cerebral perfusion pressure, and increase the potential for barotrauma and increased ICP.  Therefore, much consideration should be given prior to simply increasing PEEP beyond 10 cmH2O when one encounters troublesome ventilation parameters. Finding "ideal" PEEP was highlighted by an article in the journal Anesthesiology [6], where it was demonstrated that when 'ideal' PEEP was identified using electrical impedance tomography intraoperative oxygenation, Pdrive, and post operative lung collapse were all improved. They also determined that ideal PEEP varied greatly between patients, and those receiving 'ideal' PEEP had no adverse affects. These authors were also able to demonstrate that applying a uniform level of PEEP to all patients can be problematic.  During their recruitment process they were able to observe that a fixed PEEP of 6 cmH2O caused a wide range of lung collapse from 3 to 33% of the lung volume. At the other extreme, a fixed-PEEP of 16 cmH2O caused 5 to 52% of lung hyper distention. This study was also able to demonstrate a strong correlation between increasing BMI and higher ideal PEEP, but again, there was large variability. Tharp was [10] also able to demonstrate, that PEEP requirements also increase with the trendelburg position.

Unfortunately, the above technique of electrical impedance tomography is not available clinically.  However, Park et al.[7] studied PEEP titration to Pdrive in an RCT of patients undergoing one lung ventilation for esophagectomy. One group received "protective" ventilation parameters by using 6 mL/kg of IBW Vt and PEEP of 5 cmH2O with recruitment maneuvers while the test group had their PEEP titrated.  Starting at a PEEP of 2 cmH2O, they calculated Pdrive for the patient by using an inspiratory hold of 30% of inspiratory time to measure Pplat and then subtracted PEEP (Pdrive =Pplat-PEEP).  After every change in PEEP, then allowed ten breath cycles to occur, and then used the Pplat of the last cycle for the measurement.  After they tried PEEP 2 through 10 cmH2O, they used the PEEP at which the Pdrive was the lowest. PPCs were decreased from 12.2% in the protected ventilation group to 5.5% in the titration of Pdrive group which was statiscally significant (OR 0.4). A meta analysis of various set PEEP levels compared to individualized PEEP found that individualized PEEP was superior to set PEEP values (from low to high) in terms of oxygenation and lung compliance.  In another RCT [8] in elderly patients undergoing laparoscopic surgery, titration of best PEEP from 4 to 10 cmH2O was compared to a convention group (Vt 10 ml/kg no PEEP) and a protective ventilation group (Vt  ml/kg IBW and PEEP of 6 cmH2O).  The CV and PV groups had similar post op pulmonary profiles vs much improved profiles in patients whose PEEP was titrated to the lowest Pdrive. Similar results were found in patients having a lapx chole [9].  

Unfortunately, while it seems clear that reducing Pdrive and titrating PEEP to the lowest Pdrive in patients improve pulmonary profiles, several questions remain:  In which patients should we use these procedures, which types of surgeries, what PEEP level should be tried, what Pdrive is too high, and how often should we reverify ideal PEEP Intraoperatively?

My patient had high Peak airway pressures as well as high Pdrive.  I tried to titrate my PEEP higher and this did help reduce Pdrive, but it remained around 14 to 16 cmH2O with a PEEP as 12 to 14 cmH2O.   My patient was having a robotic VHR.  


1. Tharp WG et al.  Anesthesiology V133, issue 4, 2020

2. Bao X, Vidal Melo M. Anesthesiology V133, issue4, 2020

3. Florio G, Ferrari M, Bittner EA, De Santis Santiago R, Pirrone M, Fumagalli J, Teggia Droghi M, Mietto C, Pinciroli R, Berg S, Bagchi A, Shelton K, Kuo A, Lai Y, Sonny A, Lai P, Hibbert K, Kwo J, Pino RM, Wiener-Kronish J, Amato MBP, Arora P, Kacmarek RM, Berra L; i Crit Care. 2020 Jan 15;24(1):4. 

4. Amato MB, Meade MO, Slutsky AS, Brochard L, Costa EL, Schoenfeld DA, Stewart TE, Briel M, Talmor D, Mercat A, Richard JC, Carvalho CR, Brower RG. N Engl J Med. 2015 Feb 19;372(8):747-55.

5. Neto AS, Hemmes SN, Barbas CS, Beiderlinden M, Fernandez-Bustamante A, Futier E, Gajic O, El-Tahan MR, Ghamdi AA, Gunay E, Jaber S, Kokulu S, Kozian A, Licker M, Lin WQ, Maslow AD, Memtsoudis SG, Reis Miranda D, Moine P, Ng T, Paparella D, Ranieri VM, Scavonetto F, Schilling T, Selmo G, Severgnini P, Sprung J, Sundar S, Talmor D, Treschan T, et al.: LancetRespiratory Med 2016; 4:272–80 

6.  Pereira S, Tucci M, Morais C, Simons C, Tonelotto B, Pompeo M, Kay F, Pelosi P, Vieira J, Amato M.  Anesthesiology December 2018, Vol. 129, 1070–1081.

7. Park et al.  Anesthesiology. March 2019, Vol. 130, issue 3

8. Xu Q BMC Anesthesiology. 2022; 22:72.

9 D’Antini D, Rauseo M, Grasso S, et al. Physiological effects of the open lung approach during laparoscopic cholecystectomy: focus on driving pressure. Minerva Anestesiol. 2018;84(2):159–67.


February 19, 2022

pituitary adenoma coming for surgery

 59 year old female for D&C and hysteroscopy with a history of pituitary adenoma, empty sella syndrome, Adrenal insufficiency, HTN, OSA, and BMI of 31. The patient was taking cabergoline to inhibit the secretion of prolactin via agonism of dopamine receptors. The patient also had a history of PONV and was very concerned with this prior to surgery.


The patient had been followed for several years for her pituitary adenoma and had had no recent changes in her medical status.  I verified that her labs were within normal limits and proceeded with a general anesthetic with LMA.


The pituitary gland occupies the sella turcica of the sphenoid bone at the base of the skull, the roof of which is created by an incomplete fold of dura, the diaphragma sella, through which passes the pituitary stalk.


Hormone and site of productionTarget organ and function
Anterior pituitary 
ACTH pars distalis Adrenal glands: stimulates the glands to produce glucocorticoids and aldosterone 
GH pars distalis Musculoskeletal system: anabolic effects on bone and muscle. Promotes lipolysis, increases free fatty acid levels, and impairs glucose utilization and cellular sensitivity to insulin 
Prolactin pars distalis Mammary glands: stimulates the glands to produce milk 
Ovary: inhibits the actions of gonadotropins on the ovary 
FSH and LH pars tuberalis Gonads: stimulate the testes to produce sperm and testosterone, and the ovaries to produce eggs and oestrogen 
TSH pars tuberalis Thyroid: stimulates the gland to produce thyroid hormones 
Beta-melanocyte-stimulating hormone pars intermedia Skin: causes increased pigmentation 
Endorphins and encephalins pars intermedia Brain and immune system: inhibits pain sensations 
Posterior pituitary 
Antidiuretic hormone Kidneys: regulates the amount of water excreted by the kidneys and maintains water balance in the body 
Oxytocin Uterus: contracts the uterus during childbirth and immediately after delivery 
Mammary glands: stimulates contractions of the milk ducts in the breast leading to the let-down reflex, which moves milk to the nipple in lactating women 

The posterior pituitary is regulated directly by the hypothalamic axons which project to it and synapse with its cells. The anterior pituitary is regulated by hypothalamic tropic hormones that reach it via the portal venous system. The hypothalamic influence is mainly stimulatory, which is in turn regulated by negative feedback control exerted at the pituitary and hypothalamic level, the classical example being the feedback regulation of thyroid-stimulating hormone (TSH) by the thyroid hormones

There are two main categories that facilitate tracking the practical considerations of approaching a patient with a pituitary adenoma. Macroadenomas (>10mm) and microadenomas (<10mm).   Larger tumours can cause hypopituitarism, cranial nerve palsies, and hydrocephalous due to blockage of third ventricle outflow. Microadenomas may present with symptoms of hormonal excess, the classic example being Cushing's disease [excess of adrenocorticotropic hormone (ACTH)] or very rarely thyrotoxicosis (excess of TSH).  

The three most common hypersecreting hormonal syndromes from pituitary adenomas include:

1) Acromegaly: 20% of pituitary adenomas. These are  macroadenomas secreting excess GH resulting in a constellation of comorbidities.
Patients coming to surgery with this type of tumor will be on medications to inhibit GH production such as Somatostatin analogues, Octreotide, lanreotide or GH receptor antagonist (Pegvisomant).
2) Cushing's disease:  A pituitary corticotroph adenoma secreting excess ACTH. These represent about 7% of pituitary adenomas. These patients may arrive to surgery taking ketoconazole, metyrapone, mitotane, or aminoglutethimide. These medications inhibit the enzymes in the adrenal gland that make up the chain of synthesis of cortisol and therefore, are able to reduce hypercortisolemia.  Patient's may be arriving to surgery to undergo bilateral adrenalectomy which is required for non resesectable ACTH hypersecreting microadenomas. These patients often suffer from HTN, DM and osteoporosis (40% of patients).
In particular, patients with Cushing's disease may present with hypokalemic metabolic alkalosis. Hypokalemia occurs due to overwhelming of the enzyme 11-beta-hydroxysteroid dehydrogenase by excessive circulating cortisol, resulting in inappropriate activation of the mineralocorticoid receptor.  This receptor allows for retention of sodium at the expense of spilling potassium and hydrogen ions into the urine at the distal convoluted tubule of the kidney.
3) Prolactinoma: Medical therapy is first line with bromocriptine or cabergoline (inhibit prolactin secretion). These medications will often resolve hyperporlactinemia and reduce tumor size.  There are no perioperative care issues caused by the physiological affects of prolactinomas. These tumors are far more common in females. In men, they are often macro adenomas.



Hormone Hyposecretion

1) Adrenal cortical insufficiency: This is also known as secondary adrenal insufficiency and differs from Addison's disease in that the electrolyte disturbances are less severe. In the perioperative period IV hydrocortisone along with IV normal saline +/- IV glucose is indicated for support to avoid hypotension.

As cortisol is produced in the adrenal cortex in the zone fasciculate via stimulation from ACTH, in some rare cases (i.e. pituitary apoplexy), the pituitary gland is rendered incapable of producing ACTH. While in secondary adrenal insufficiency the sodium and potassium are often normal, although in some instances, a dilution hyponatremia develops due to excess ADH secretion from absence of cortisol.  Dehydration and hyperkalemia are typical of primary adrenal cortical insufficiency due to faulty aldosterone secretion as well.  However, aldosterone is not primarily under the control of the PG, and therefore, not typical of secondary adrenal insufficiency.




In cases of addisonian crisis from secondary adrenal insufficiency as seen from a PG problem can be treated with dexamethasone 8 mg or hydrocortisone.  Since in secondary adrenal insufficiency aldosterone is adequate, the mineralocorticoid effects of hydrocortisone are not critical, and a pure glucocorticoid such as decadron is adequate for treatment.  However, NS should be infused as well, as opposed to LR, as hyponatremia may accompany this syndrome from SIADH.

2) Hypothyroidism:  Pituitary hypothyroidism tends to be less severe than primary thyroid failure. However, patients will be more sensitive to and less able to metabolize anesthetic medications. This can result in induction of anesthesia with very low dosages as well as prolonged sleep after discontinuation of anesthetic medications.   Clinical response to thyroid replacement therapy may take 10 days, although more rapid correction can be achieved with i.v. L-iodothyronine (T3). Unfortunately, there is a significant risk of precipitating myocardial ischaemia and heart failure.  Furthermore, Thyroid hormone replacement has to be done very cautiously in patients with impaired adreno-corticotrophic hormone ACTH reserves as it can precipitate an adrenal crisis. Therefore, glucocorticoid cover is essential before proceeding with thyroid hormone replacement.

3)  Central Diabetes Insipidus:  Far less likely to be encountered in the perioperative period. The result of failure of secretion of ADH. It is treated with desmopressin, a synthetic analogue of ADH that has a longer half life and which lacks the vasoconstricting properties of the endogenous hormone. Although desmopressin is usually administered orally or intra-nasally, after operation it can be given as a subcutaneous or intra-muscular injection. Failure to secrete oxytocin only becomes clinically evident during and after childbirth, and is not relevant in the acute setting.7
 

Surgical stress and hormonal changes


Pituitary
Adrenal
Pancreatic
Others
Increased secretion Growth hormone (GH) Catecholamines Glucagon Renin 
 Adrenocorticotrophic hormone (ACTH) Cortisol   
 β-Endorphin Aldosterone   
 Prolactin    
 Arginine vasopressin (posterior pituitary) (AVP)    
Unchanged secretion Thyroid stimulating hormone (TSH)    
 Luteinizing hormone (LH)    
 Follicle stimulating hormone (FSH)    
Decreased secretion   Insulin Testosterone 
    Oestrogen 
    Tri-iodothyronine (T3)

Opioids can suppress the hypothalamic and pituitary hormone response to surgery.  However, to cause complete suppression, very large doses are required (i.e. ~50 mcg/kg).

Acute IV opioid administration can have a stimulatory effect on prolactin secretion mediated by the mu-,Kappa-, and sigmoid opioid receptors in the hypothalamus.  In cases of prolactinemia induced by opioids, bromocriptine has been used successfully to decrease prolactin levels.

This patient was taking cabergoline a dopamine 2 receptor agonist.  Cabergoline has been found to be effective in 80% of women with prolactinomas.  Bromocriptine has lost favor mainly due to pharmacokinetic issues where it is required up to 3 or 4 times a day.  Cabergoline is long acting requiring dosing as little as twice a week. It is important to note that PONV can be affected by stimulation of D2 and D3 receptors. Antagonism of these receptors may decrease PONV. The mechanism involves blocking adenylate cyclase to reduce the amount of cAMP in neurons in the nucleus tractus solitarius and area postrema.  Commonly used D2 antagonists include reglan, and a newer agent name Barhemsys (amusulpride).  In this patient with a concern for PONV and taking a D2 receptor agonist that was long acting, rescue treatment with any D2 receptor blocker may prove less effective.  Therefore, with the patient's permission a scopolamine patch was placed on the skin prior to rolling into the operating room.  Opioids were minimized, ketorolac was provided to reduce opioid requirements, dexamethasone 4mg and zoltan 4 mg were given as prophylaxis. The patient did not experience any PONV. If the patient had required rescue therapy, promethazine was ordered for rescue.  Barhemsys is a newer alternative which has been shown to be moderately effective for rescue therapy in patients who have already received prophylaxis.  Unfortunately, Barhemsys is a D2/3 antagonist which presents two potential concerns in this patient. 1) it may not be able to bind to the D2 receptor given the presence of cabergoline (d2 agonist). 2) It can induce increased prolactin levels in normal patients.  However, it is not clear at all, that this would be a problem in a patient who is already properly treated with cabergoline.

Pituitary adenomas represent a potential large constellation of syndromes and diseases processes.  A careful understanding of the type of adenoma along with its included pathophysiology is important prior to providing anesthesia. Fortunately, most pituitary adenomas are prolactinomas which tend to be benign and very responsive to medical therapy with dopamine 2 agonists.  It must be recognized that alternative pharmacotherapy for PONV must be considered as the d2 agonist in these patients will likely make antagonism of the D2 receptor impossible.