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The Cushing reflex and the vasopressin-mediated hemodynamic response to increased intracranial pressure during acute elevations in intraabdominal pressure
Surgery xxx (2019) 1e6
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The Cushing reflex and the vasopressin-mediated hemodynamic response to increased intracranial pressure during acute elevations in intraabdominal pressure Lisandro Montorfano, MDa, Giulio Giambartolomei, MDa, David Romero Funes, MDa, Emanuele Lo Menzo, MD, PhDa, Fernando Dip, MDa,b, Kevin P. White, MD, PhDc, Raul J. Rosenthal, MDa,* a
Section of Minimally Invasive Surgery, Department of General Surgery, Cleveland Clinic Florida, Weston, FL stico y Tratamiento, Buenos Aires, Argentina Instituto Argentino de Diagno c ScienceRight Research Consultations, London, ON, Canada b
a r t i c l e i n f o
a b s t r a c t
Article history: Accepted 11 October 2019 Available online xxx
Background: Abdominal compartment syndrome has been linked to detrimental hemodynamic side effects that include increased intracranial pressure and diminished renal function, but the mechanisms behind this continue to be elucidated. In this study, we sought to investigate any direct association between acute elevations in intra-abdominal pressure and intracranial hypertension during experimentally induced abdominal compartment syndrome and between acutely elevated intracranial pressure and the hemodynamic response that might be elicited by a vasopressin-induced Cushing reflex affecting urine osmolality and urine output. The aim of this study is to explain the Cushing reflex and the vasopressin-mediated hemodynamic response to intracranial pressure during acute elevations in intraabdominal pressure. Methods: We measured intra-abdominal pressure, intrathoracic pressure, optic nerve sheath diameter as an indirect sign of intracranial pressure, vasopressin levels in blood, urine osmolality, and urine output at 4 time points during surgery in 16 patients undergoing sleeve gastrectomy for morbid obesity. Values for the 4 time points were compared by repeated-measures analysis of variance. Results: More than 50-fold elevations in serum vasopressin paralleled increases in optic nerve sheath diameter, rising throughout prepneumoperitoneum and tapering off afterward, in conjunction with a marked decrease in urine but not serum osmolality. Mean arterial pressure rose transiently during pneumoperitoneum without elevated positive end-expiratory pressure but was not significantly elevated thereafter. Conclusions: These findings support our hypothesis that the oliguric response observed in abdominal compartment syndrome might be the result of the acutely elevated intra-abdominal pressure triggering increased intrathoracic pressure, decreased venous outflow from the central nervous system, increased intracranial pressure, and resultant vasopressin release via a Cushing reflex. © 2019 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Introduction In 1901, American neurosurgeon Harvey Cushing described a phenomenon by which increased intracranial pressure (ICP), often resulting from a head injury, ultimately can lead to paradoxical
Reprints will not be available from the author. * Reprint requests: Raul J. Rosenthal, MD, Cleveland Clinic Florida, 2950 Cleveland Clinic Blvd, Weston, FL 33331. E-mail address: [email protected] (R.J. Rosenthal).
hypertension and bradycardia as well as altered breathing, potentially culminating in apnea.1 Though the mechanisms behind these paradoxical reactions are complex,2 they are believed to at least partially result from variable and opposing contributions of the sympathetic and parasympathetic nervous systems as protective effects against cerebral ischemia, combined with direct mechanical effects. Recently, oliguria has been identified as a systemic sequela of the Cushing’s reflex.3 Abdominal compartment syndrome, characterized by an acute elevation in intra-abdominal pressure (IAP), has been demonstrated
https://doi.org/10.1016/j.surg.2019.10.006 0039-6060/© 2019 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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to be linked to detrimental systemic side effects which include, similar to the Cushing’s reflex, cardiovascular, respiratory, renal, and neurological involvement.4 Several studies, mostly in experimental settings, have been conducted in an attempt to better understand and define the underlying mechanisms that regulate the pathophysiological changes triggered by acute elevations in IAP.5e7 Over the last few decades, this topic has become of interest because of the widespread use of laparoscopy during acute elevations of IAP, during which a pneumoperitoneum is created by insufflating carbon dioxide gas (CO2). In previous large-animal and human studies, we have demonstrated that acute elevations in IAP can trigger acute elevations in ICP that will, in turn, result in arterial hypertension.5,8e11 The latter appears to be a hemodynamic response to maintain cerebral blood flow. In our prior research, however, we were unable to demonstrate that the abovementioned response might have been triggered by increased levels of vasopressin.9,12e14 In the past, studies to understand intracranial changes during abdominal compartment syndrome were limited by the invasiveness of ICP measurements. Lately, however, several studies have validated the use of optic nerve ultrasound as a non-invasive, accurate, safe, reproducible, and cost-effective tool for ICP via the measurement of optic nerve sheath diameter (ONSD), thereby reducing the potentially harmful consequences of invasive transcranial measurements.12,15,16 Based upon these premises, and armed with the new technique of ONSD measurement, the primary endpoint of the current study was to investigate any direct correlation between acute elevations in IAP and intracranial hypertension, which could trigger similar hemodynamic changes observed during
DECREASED ABSORPTION OF SPINAL CSF FROM SPINAL ARACHNOID VILLI
INCREASED PRESSURE OF CSF COMPARTMENT
DECREASED CSF ABSORPTION FROM ARACHNOID VILLI
INCREASED VENOUS PRESSURE IN SAGITAL SINUS AND CNS
DECREASED VENOUS DRAINAGE FROM CSF DECREASED VENOUS DRAINAGE OF THE LUMBAR PLEXUS AND YUGULAR VEINS
Methods After institutional review board approval and following Health Insurance Portability and Accountability guidelines, we conducted a prospective, observational study involving patients selected for elective bariatric surgery. Between 2017 and 2019, all patients undergoing sleeve gastrectomy to treat severe obesity were enrolled in this study and had several parameters tested, as explained below. Exclusion criteria were age <18 years, pre-existing renal failure, and failure to provide written, informed consent, as indicated in the Declaration of Helsinki. Our a priori hypothesis was that hemodynamic changes observed during acute elevations of IAP are triggered by intracranial hypertension and the Cushing reflex, mediated by release of vasopressin (see Fig 1). To assess this hypothesis, we identified 4 different stages during which we would measure the following 6 parameters: (1) IAP, (2) intrathoracic pressure, (3) ONSD as an indirect sign of ICP, (4) vasopressin levels in blood, (5) urine osmolality, and (6) urine output. These measurements were performed at different levels of pneumoperitoneal and intrathoracic pressure, after gaining intravenous access, with the patient anesthetized and ventilated via an endotracheal tube, in a supine position, and after a Foley
INCREASED INTRACRANIAL PRESSURE CSF EFFECT
ARTERIAL CEREBROVASCULAR DILATATION
VQ MISMATCH COMPRESSION OF OF LOWER LOBE OF THE LUNGS
INCREASED INTRATHORACIC PRESSURE
VENOUS EFFECT INFERIOR VENA CAVA COMPRESSION
abdominal compartment syndrome. A second endpoint of this study was to investigate any correlation between acutely elevated ICP and the hemodynamic response that might be elicited by a Cushing reflex mediated by vasopressin release, affecting urine osmolality and urine output.
VASOPRESSIN RELEASE ARTERIAL EFFECT INCREASED CARDIAC PRELOAD AND EJECTION FRACTION
DECREASED URINE OUTPUT
HYPERCARBIA
PERITONEAL ABSORPTION OF CO2
INCREASED CEREBRAL PERFUSION PRESSURE CO2 H30
INCREASED IAP CRANIAL DISPLACEMENT DIAPHRAGM
Fig 1. Cushing reflex mediated by release of vasopressin during acute elevations of IAP. CSF, cerebrospinal fluid; VQ, ventilation-perfusion.
L. Montorfano et al. / Surgery xxx (2019) 1e6
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Table I Vasopressin and osmolality changes after acute elevation of IAP N ¼ 16
Baseline*
Pneumoperitoneumy
z
PEEPx
k
Vasopressin pg/mL Serum osmolality mosm/kg Urine osmolality mosm/kg
2.37 ± 5.23 353.13 ± 192.12 605.47 ± 220.2
45.48 ± 16.83 289.33 ± 7.31 527.6 ± 246.5
.0001 .1605 .0291
54.75 ± 16.18 290.56 ± 2.56 539.86 ± 222.1
.0001 .1625 .0121
P value
P value
END¶ 31.57 ± 18.04 326.60 ± 145.81 493.1 ± 213.64
Data are presented as mean ± standard deviation. * Baseline ¼ with no pneumoperitoneum. y Pneumoperitoneum ¼ 10e15 min after insufflation of the pneumoperitoneum with CO2 to 15 mmHg intraabdominal pressure, with PEEP at 5 cmH2O. z P value for baseline versus pneumoperitoneum. x PEEP ¼ 10e15 min after stabilization of PEEP at 10 cmH2O, with the pneumoperitoneum still at 15 mmHg. k P value for baseline versus PEEP. ¶ END ¼ 10e15 min after complete desufflation of the pneumoperitoneum, at basal mechanical ventilation.
catheter was in place in the urinary bladder. The 4 different stages were as follows: (1) Stage 1: baseline, with no pneumoperitoneum; (2) Stage 2: 10 to 15 minutes after insufflation of the pneumoperitoneum with CO2 to 15 mmHg IAP, with positive endexpiratory pressure (PEEP) at 5 cm H2O; (3) Stage 3: 10 to 15 minutes after stabilization of PEEP at 10 cm H2O, with the pneumoperitoneum still at 15 mmHg; (4) Stage 4: 10 to 15 minutes after complete desufflation of the pneumoperitoneum, at basal mechanical ventilation. The measurements included these 6 parameters: (1) IAP: assessed via a laparoscopic insufflator with highpressure nozzles directing CO2 into the cannula until the desired IAP of 15 mmHg (standard for all laparoscopic procedures) is achieved. The laparoscopic insufflator has a continuous flow circuit that is activated and evacuates intraabdominal gas, recirculating and detecting minor changes in IAP in real time, adjusting the flow, either by insufflating more gas into the abdominal cavity or venting it out of the access port to keep the IAP stable. (2) Intrathoracic pressure: indirectly measured by PEEP on a General Electric Aisys Ventilator (General Electric, Boston, MA) that delivers oxygen and anesthetic gases to the patient and removes CO2, providing controlled mechanical ventilation. A #7.0 (female patients) or #8.0 (male patients) Shiley Cuffed Basic Endotracheal Tube (Medtronic, Minneapolis, MN) d a latex-free, soft flexible polyvinyl chloride tube d was used for this study. (3) Urine collection: through a Foley catheter from the beginning of surgery to postoperative Day 1. Urine osmolality was assessed at set time points and hourly urine output was measured for at least 24 hours to evaluate expected significant variations even after the procedure ends, since renal adaptation could take longer.
(4) Serum/plasma collection: blood draws to evaluate specific values of plasma vasopressin (anti-diuretic hormone) and serum osmolality. (5) Mean arterial pressure (MAP): non-invasive standard monitoring during anesthesia (6) PEEP: Anesthesiologists routinely adapt PEEP to maintain optimal ventilation, especially in obese patients and during laparoscopic procedures ONSD: a 7.5-MHz linear ultrasound probe was used to measure the diameter of the optic nerve sheath, 3 mm behind the globe; with 1 trained study personnel (MD), supervised by the anesthesiologist, taking noninvasive sonographic pictures. The ONSD was measured from each captured picture and the measurement was recorded in the patient’s chart. The ONSD was measured before pneumoperitoneum (base line measurement, 0 minute), at 15 and 30 minutes, and after deflation. Normal ONSD was estimated to be less than 4.5 mm based on previous literature. Higher values (4.5 mm) are considered abnormal. We considered each patient his/her own control to evaluate ONSDs during the different stages of
Statistical analysis For our power analysis, our expectation was that we would observe a 20% to 25% increase in the normal value of vasopressin versus baseline. We also made the following assumptions: That the normal range value of vasopressin is from 1 to 4 pg/mL. According to the number stated in the reference articles, we assumed a coefficient of variation of 0.455. A type I error rate for the overall test comparing the 3 groups of 0.05. That data would be normally distributed. Power, b ¼ 80%. Repeated measures analysis of variance was used to compare mean levels of vasopressin across the 4 different conditions, with
Table II Changes in MAP and ONSD after acute elevation of IAP N ¼ 16
Baseline*
Pneumoperitoneumy
P valuez
PEEPx
P valuek
END¶
MAP (mmHg) ONSD left ONSD right
80.38 ± 21.0 0.37 ± 0.04 0.37 ± 0.05
93.0 ± 14.3 0.44 ± 0.04 0.44 ± 0.00
.021 .0003 .0018
90.56 ± 15.1 0.49 ± 0.16 0.53 ± 0.18
.1652 .0079 .0035
89.69 ± 21.8 0.34 ± 0.04 0.37 ± 0.038
Data are presented as mean ± standard deviation. * Baseline ¼ with no pneumoperitoneum. y Pneumoperitoneum ¼ 10e15 min after insufflation of the pneumoperitoneum with CO2 to 15 mmHg IAP, with PEEP at 5 cmH2O; x PEEP ¼ 10e15 min after stabilization of PEEP at 10 cmH2O, with the pneumoperitoneum still at 15 mmHg. ¶ END ¼ 10e15 min after complete desufflation of the pneumoperitoneum at basal mechanical ventilation. z P value for baseline versus pneumoperitoneum. k P value for baseline versus PEEP Mean ± standard deviation.
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reading (Fig 2). Meanwhile, the ONSD, reflective of ICP, rose and fell in parallel with the rise and fall in vasopressin, averaging abovenormal levels in both the right and left eyes during Stage 3 (Fig 3). Discussion
Fig 2. Changes in serum vasopressin with pneumoperitoneum. Baseline ¼ with no pneumoperitoneum; Pneumoperitoneum ¼ 10e15 min after insufflation of the pneumoperitoneum with CO2 to 15 mmHg IAP, with PEEP at 5 cmH2O; PEEP ¼ 10e15 minutes after stabilization of PEEP at 10 cmH2O, with the pneumoperitoneum still at 15 mmHg; END ¼ 10e15 minutes after complete desufflation of the pneumoperitoneum, at basal mechanical ventilation.
comparisons between any 2 conditions assessed using paired t tests. All tests were 2-tailed. Results A total of 16 patients were enrolled at the time of the analysis. Of these, 11 were female and 5 were male. Mean patient age was 45.0 ± 10.0 years. The mean preoperative body mass index was 41.1 (±4.4) kg/ m2. All 16 (100%) laparoscopic procedures were sleeve gastrectomies. MAP and serum osmolality did not exhibit any statistically significant change when measured across the 4 data-collection points during the intervention. On the other hand, a significant reduction in urine osmolality was observed (P ¼ .03 and P ¼ .01 at Stages 2 and 3, relative to baseline) (Tables I and II). Serum vasopressin was 50-fold higher than baseline when measured during pneumoperitoneum (P < .001 for both Stages 2 and 3, relative to baseline), with 56% (n ¼ 9) of patients having a vasopressin level >65pg/mL when measured at an elevated PEEP. This level remained significantly elevated, relative to baseline, throughout the procedure, albeit trending downward at the Stage 4
Fig 3. Changes in ONSD with pneumoperitoneum. Baseline ¼ with no pneumoperitoneum; Pneumoperitoneum ¼ 10e15 minutes after insufflation of the pneumoperitoneum with CO2 to 15 mmHg IAP, with PEEP at 5 cmH2O; PEEP ¼ 10e15 minutes after stabilization of PEEP at 10 cmH2O, with the pneumoperitoneum still at 15 mmHg; END ¼ 10e15 minutes after complete desufflation of the pneumoperitoneum, at basal mechanical ventilation.
The side effects of acute and prolonged elevations in IAP during CO2 pneumoperitoneum or abdominal compartment syndrome have been the subject of extensive research.4,5,7e10,14,17 In previous studies, we demonstrated that the OSND, measured with ultrasound, will enlarge after establishing acute elevations of IAP while creating a CO2 pneumoperitoneum.12,13 Two mechanisms have been postulated that could explain the correlation between elevations in IAP and ICP. An early mechanical or venous stage is explained as compression of the inferior vena cava via elevation and cranial displacement of the diaphragm caused by the insufflation of the pneumoperitoneum, which reduces venous drainage from the lumbar plexus and central nervous system, thereby increasing the pressure within the brain and spinal canal.7,18 A late chemical or arterial mechanism is related to CO2 diffusion through the peritoneal membrane into the arterial vasculature, which results in an increase in PaCO2 and reflex vasodilation in the central nervous system (CNS) that leads to an increase in ICP, following the Monroe-Kellie hypothesis.5,6 The effects of elevated ICP on renal hemodynamics have been studied under experimental and clinical settings, though they remain incompletely understood.12,16 Decreased cardiac output and increased vascular and renal resistance have been proposed as mechanisms underlying the sudden impairment of renal function following increases in IAP, though correcting cardiac output has not been found to restore normal renal function.19 Placing ureteral stents to counteract high pressure compression on ureters also has failed to restore normal urine output.4 Catecholamines and vasopressin release have been proposed to play an important role in this mechanism.4,13e15,20 Two studies on this topic have been conducted with the aim of identifying significant antidiuretic hormone changes during laparoscopy and its positional changes.13,21 Both studies showed a variable but nonsignificant increase in plasma vasopressin concentration after insufflation causing pneumoperitoneum. What could have been in the past an obstacle to better explain the hemodynamic response to acute elevations in ICP was the measurement of the ICP itself, since it was only feasible by invasive transcranial techniques. Lately, however, several studies have validated the use of optic nerve ultrasound as a noninvasive, accurate, safe, reproducible, and cost-effective tool for assessing ICP, reducing potentially harmful consequences of invasive transcranial measurements.12,15,16 In our study, the ONSD increased drastically (over 20-fold) when pneumoperitoneum was established and during the elevated PEEP phase. Along with this, it was expected that urine output would decrease and urine osmolality increase. This is because the renal filtration gradient is the mechanical force across the glomerulus and equals the difference between the glomerular filtration pressure and the proximal tubular pressure. In the presence of intra-abdominal hypertension, proximal tubular pressure may be assumed equal to IAP; thus, the glomerular filtration pressure can be estimated as the MAP minus 2 times the IAP. Thus, changes in the IAP will have a greater impact upon renal function and urine production than those caused by changes in MAP.14,18,19,22,23 As a result, increased urine osmolarity would be expected to be one of the first visible signs of intra-abdominal hypertension. In our series, urine osmolality decreased. The reason for this is unclear but may be multifactorial. To begin with, all of our patients were obese, and the majority were morbidly obese, and obesity, in itself, has been shown to cause chronic kidney disease that could have altered the kidneys’ ability to concentrate urine.24 In addition, the vast majority of our patients had diabetes mellitus, and their
L. Montorfano et al. / Surgery xxx (2019) 1e6
serum glucose levels may have spiked during the stress of surgery, causing urine to dilute. Another potential explanation is fluid overload from anesthesia upon induction. In our patients, serum vasopressin was more than 20-fold higher than baseline when measured during pneumoperitoneum and 56% (n ¼ 9) of patients had a vasopressin level >65 pg/mL when measured at an elevated PEEP. As observed in other similar clinical scenarios like intracranial bleeding, when there is an acute elevation of ICP, the Cushing reflex is activated via the release of vasopressin, which is done to increase cardiac preload and ejection fractions, thereby maintaining cerebral blood flow.7,9,10,21,25,26 This latter finding supports our hypothesis that the oliguric response observed in abdominal compartment syndrome might be the result of the acute elevation in IAP that, in turn, triggers increased intrathoracic pressure resulting in decreased venous outflow from the CNS via the lumbar and jugular veins, which in turn results in acute elevations of ICP that could create cerebral ischemia. To prevent the abovementioned insult, the CNS, by means of a Cushing reflex, will release vasopressin to mobilize venous blood and augment the preload, which will increase the ejection fraction and maintain cerebral blood flow (see Fig 1). The reason that vasopressin levels remain high is related to the arterial or chemical phase of ICP, in turn related to the continued cerebrovascular dilatation triggered by the hypercarbia that results from the absorption of peritoneal CO2. The latter will require a longer period of time to return to normal values, dependent upon the patient’s ventilation status and level of sedation. This study is, to our knowledge, the first literature report to analyze the mechanisms of action and to attempt to explain the oligo-anuric response to abdominal compartment syndrome that is triggered by elevated ICP and released vasopressin. We further hypothesize that, by administering vasopressin antagonists, renal impairment and acute kidney injury might be prevented, as has already been shown in a rat model.22 Our study has several weaknesses. Among them is that ours is a small patient population of nonrandomized patients; as such, we cannot rule out random error or bias in our results. A larger patient population would have provided us with more powerful statistical analysis to document causative effects. Another weakness related to the small number of subjects is that we did not adjust for multiple comparisons; this said, the fall in urine osmolality was our only positive finding that would have failed to satisfy a Bonferroniadjusted significance threshold of P .008. Third, all of our patients were obese (most morbidly obese, with a mean body mass index of approximately 41 kg/m2) and most likely had diabetes, hypertension, or both, related to their obesity; as such, the current findings would need to be reproduced in other nonobese populations to verify their general applicability. Fourth, likely related to obesity, diabetes, or both and as explained earlier, we observed a decrease rather than the expected increase in urine osmolality in the presence of elevated vasopressin. Fifth, it is possible that insufflation using CO2 might have increased arterial paCO2 and that this, in turn, might have altered ICP. Unfortunately, the use of an inert gas like helium has not yet been approved for use for pneumoperitoneum at our hospital. Finally, although our data are strongly suggestive of a Cushing effect, more definitive proof of this effect would have been to administer some form of vasopressor blockade. This was not part of normal intraoperative care, however, and could have posed some risk to patients. In conclusion, Harvey Cushing is attributed with having established neurosurgery as a surgical subspecialty and, over more than 2,000 brain tumor operations, to have reduced neurosurgical mortality from 50% to only 8%.27 He also described, almost 120 years ago, Cushing’s reflex. In our series of 16 obese patients undergoing sleeve gastrectomies, we found that a Cushing’s reflexlike response might also be at play in patients with abdominal
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compartment syndrome. Specifically, acute elevations in IAP, observed during laparoscopic procedures triggered by CO2 pneumoperitoneum, appeared to increase intrathoracic pressure and elevate PEEP, resulting in an acute elevation of ICP, manifested as enlarged ONSD. Such increases in IAP may increase ICP without altering cerebral perfusion pressure. The latter might be responsible for a Cushing reflex-type response mediated by acute elevations in serum vasopressin levels. Additional studies are underway with more patients to confirm these findings and explain them further. Funding/Support The authors have no funding disclosures to report. Conflict of interest/Disclosure The authors have no conflicts of interest to report. Acknowledgments The authors have no acknowledgments to report. References 1. Cushing H. Concerning a definite regulatory mechanism of the vaso-motor center which controls blood pressure during cerebral compression. Bull Johns Hopkins Hosp. 1901;12:290e292. 2. Beiner JM, Olgivy CS, DuBois AB. Cerebral blood flow changes in response to elevated intracranial pressure in rabbits and bluefish: a comparative study. Comp Biochem Physiol A Physiol. 1997;116:245e252. 3. Leyssens K, Mortelmans T, Menovsky T, Abramowicz D, Twickler MTB, Van Gaal L. The Cushing reflex: Oliguria as a reflection of an elevated intracranial pressure. Case Rep Nephrol. 2017;2017:2582509. 4. Papavramidis TS, Marinis AD, Pliakos I, Kesisoglou I, Papavramidou N. Abdominal compartment syndrome - intra-abdominal hypertension: Defining, diagnosing, and managing. J Emerg Trauma Shock. 2011;4:279e291. 5. Ben-Haim M, Mandeli J, Friedman RL, Rosenthal RJ. Mechanisms of systemic hypertension during acute elevation of intraabdominal pressure. J Surg Res. 2000;91:101e105. 6. Kamine TH, Elmadhun NY, Kasper EM, Papavassiliou E, Schneider BE. Abdominal insufflation for laparoscopy increases intracranial and intrathoracic pressure in human subjects. Surg Endosc. 2016;30:4029e4032. 7. Rosenthal RJ, Hiatt JR, Phillips EH, Hewitt W, Demetriou AA, Grode M. Intracranial pressure. Effects of pneumoperitoneum in a large-animal model. Surg Endosc. 1997;11:376e380. 8. Rosenthal RJ, Friedman RL, Phillipa EH. Intra-abdominal pressure, intracranial pressure, and hemodynamics: a central nervous system-regulated response. In: Rosenthal RJ, Friedman RL, Phillipa EH, eds. The Pathophysiology of Pneumoperitoneum. Berlin: Springer; 1998:85e98. 9. Rosenthal RJ, Friedman RL, Kahn AM, et al. Reasons for intracranial hypertension and hemodynamic instability during acute elevations of intra-abdominal pressure: observations in a large animal model. J Gastrointest Surg. 1998;2:415e425. 10. Rosin D, Rosenthal RJ. Adverse hemodynamic effects of intraabdominal pressure-is it all in the head? Int J Surg Investig. 2001;2:335e345. 11. Mann C, Boccara G, Pouzeratte Y, et al. The relationship among carbon dioxide pneumoperitoneum, vasopressin release, and hemodynamic changes. Anesth Analg. 1999;89:278e283. 12. Dip F, Nguyen D, Rosales A, et al. Impact of controlled intraabdominal pressure on the optic nerve sheath diameter during laparoscopic procedures. Surg Endosc. 2016;30:44e49. 13. Dip F, Nguyen D, Sasson M, Lo Menzo E, Szomstein S, Rosenthal R. The relationship between intracranial pressure and obesity: an ultrasonographic evaluation of the optic nerve. Surg Endosc. 2016;30:2321e2325. 14. Rosin D, Brasesco O, Varela J, et al. Low-pressure laparoscopy may ameliorate intracranial hypertension and renal hypoperfusion. J Laparoendosc Adv Surg Tech A. 2002;12:15e19. 15. Rajajee V, Vanaman M, Fletcher JJ, Jacobs TL. Optic nerve ultrasound for the detection of raised intracranial pressure. Neurocrit Care. 2011;15: 506e515. 16. Kimberly HH, Shah S, Marill K, Noble V. Correlation of optic nerve sheath diameter with direct measurement of intracranial pressure. Acad Emerg Med. 2008;15:201e204. 17. Viinamki O, Punnonen R. Vasopressin release during laparoscopy: role of increased intra-abdominal pressure. Lancet. 1982;1:175e176. 18. Lindberg F, Bergqvist D, Bjorck M, Rasmussen I. Renal hemodynamics during carbon dioxide pneumoperitoneum: an experimental study in pigs. Surg Endosc. 2003;17:480e484.
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19. Harman PK, Kron IL, McLachlan HD, Freedlender AE, Nolan SP. Elevated intraabdominal pressure and renal function. Ann Surg. 1982;196:594e597. 20. Rajajee V, Thyagarajan P, Rajagopalan RE. Optic nerve ultrasonography for detection of raised intracranial pressure when invasive monitoring is unavailable. Neurol India. 2010;58:812e813. 21. Fuchs EC, Forni C. The influence of secondary midbrain lesions and of the Cushing reflex relative to the prognosis of patients in traumatology (e.g. the epidural hematoma). J Neurosurg Sci. 1974;18:26e31. 22. Dolgor B, Kitano S, Yoshida T, Bandoh T, Ninomiya K, Matsumoto T. Vasopressin antagonist improves renal function in a rat model of pneumoperitoneum. J Surg Res. 1998;79:109e114. 23. Gudmundsson FF, Gislason HG, Myking OL, Viste A, Grong K, Svanes K. Hormonal changes related to reduced renal blood flow and low urine output
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under prolonged increased intra-abdominal pressure in pigs. Eur J Surg. 2002;168:178e186. Funes DR, Blanco DG, Gomez CO, et al. Metabolic surgery reduces the risk of progression from chronic kidney disease to kidney failure. Ann Surg. 2019;279: 511e518. Fassot C, Lambert G, Elghozi JL, Lambert E. Impact of the renin-angiotensin system on cerebral perfusion following subarachnoid haemorrhage in the rat. J Physiol. 2001;535:533e540. Widmayer MA, Browning JL, Gopinath SP, Robertson CS, Baskin DS. Increased intracranial pressure is associated with elevated cerebrospinal fluid ADH levels in closed-head injury. Neurol Res. 2010;32:1021e1026. Black PM. Harvey Cushing at the Peter Bent Brigham Hospital. Neurosurgery. 1999;45:990e1001.
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The Cushing reflex and the vasopressin-mediated hemodynamic response to increased intracranial pressure during acute elevations in intraabdominal pressure Lisandro Montorfano, MDa, Giulio Giambartolomei, MDa, David Romero Funes, MDa, Emanuele Lo Menzo, MD, PhDa, Fernando Dip, MDa,b, Kevin P. White, MD, PhDc, Raul J. Rosenthal, MDa,* a
Section of Minimally Invasive Surgery, Department of General Surgery, Cleveland Clinic Florida, Weston, FL stico y Tratamiento, Buenos Aires, Argentina Instituto Argentino de Diagno c ScienceRight Research Consultations, London, ON, Canada b
a r t i c l e i n f o
a b s t r a c t
Article history: Accepted 11 October 2019 Available online xxx
Background: Abdominal compartment syndrome has been linked to detrimental hemodynamic side effects that include increased intracranial pressure and diminished renal function, but the mechanisms behind this continue to be elucidated. In this study, we sought to investigate any direct association between acute elevations in intra-abdominal pressure and intracranial hypertension during experimentally induced abdominal compartment syndrome and between acutely elevated intracranial pressure and the hemodynamic response that might be elicited by a vasopressin-induced Cushing reflex affecting urine osmolality and urine output. The aim of this study is to explain the Cushing reflex and the vasopressin-mediated hemodynamic response to intracranial pressure during acute elevations in intraabdominal pressure. Methods: We measured intra-abdominal pressure, intrathoracic pressure, optic nerve sheath diameter as an indirect sign of intracranial pressure, vasopressin levels in blood, urine osmolality, and urine output at 4 time points during surgery in 16 patients undergoing sleeve gastrectomy for morbid obesity. Values for the 4 time points were compared by repeated-measures analysis of variance. Results: More than 50-fold elevations in serum vasopressin paralleled increases in optic nerve sheath diameter, rising throughout prepneumoperitoneum and tapering off afterward, in conjunction with a marked decrease in urine but not serum osmolality. Mean arterial pressure rose transiently during pneumoperitoneum without elevated positive end-expiratory pressure but was not significantly elevated thereafter. Conclusions: These findings support our hypothesis that the oliguric response observed in abdominal compartment syndrome might be the result of the acutely elevated intra-abdominal pressure triggering increased intrathoracic pressure, decreased venous outflow from the central nervous system, increased intracranial pressure, and resultant vasopressin release via a Cushing reflex. © 2019 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Introduction In 1901, American neurosurgeon Harvey Cushing described a phenomenon by which increased intracranial pressure (ICP), often resulting from a head injury, ultimately can lead to paradoxical
Reprints will not be available from the author. * Reprint requests: Raul J. Rosenthal, MD, Cleveland Clinic Florida, 2950 Cleveland Clinic Blvd, Weston, FL 33331. E-mail address: [email protected] (R.J. Rosenthal).
hypertension and bradycardia as well as altered breathing, potentially culminating in apnea.1 Though the mechanisms behind these paradoxical reactions are complex,2 they are believed to at least partially result from variable and opposing contributions of the sympathetic and parasympathetic nervous systems as protective effects against cerebral ischemia, combined with direct mechanical effects. Recently, oliguria has been identified as a systemic sequela of the Cushing’s reflex.3 Abdominal compartment syndrome, characterized by an acute elevation in intra-abdominal pressure (IAP), has been demonstrated
https://doi.org/10.1016/j.surg.2019.10.006 0039-6060/© 2019 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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to be linked to detrimental systemic side effects which include, similar to the Cushing’s reflex, cardiovascular, respiratory, renal, and neurological involvement.4 Several studies, mostly in experimental settings, have been conducted in an attempt to better understand and define the underlying mechanisms that regulate the pathophysiological changes triggered by acute elevations in IAP.5e7 Over the last few decades, this topic has become of interest because of the widespread use of laparoscopy during acute elevations of IAP, during which a pneumoperitoneum is created by insufflating carbon dioxide gas (CO2). In previous large-animal and human studies, we have demonstrated that acute elevations in IAP can trigger acute elevations in ICP that will, in turn, result in arterial hypertension.5,8e11 The latter appears to be a hemodynamic response to maintain cerebral blood flow. In our prior research, however, we were unable to demonstrate that the abovementioned response might have been triggered by increased levels of vasopressin.9,12e14 In the past, studies to understand intracranial changes during abdominal compartment syndrome were limited by the invasiveness of ICP measurements. Lately, however, several studies have validated the use of optic nerve ultrasound as a non-invasive, accurate, safe, reproducible, and cost-effective tool for ICP via the measurement of optic nerve sheath diameter (ONSD), thereby reducing the potentially harmful consequences of invasive transcranial measurements.12,15,16 Based upon these premises, and armed with the new technique of ONSD measurement, the primary endpoint of the current study was to investigate any direct correlation between acute elevations in IAP and intracranial hypertension, which could trigger similar hemodynamic changes observed during
DECREASED ABSORPTION OF SPINAL CSF FROM SPINAL ARACHNOID VILLI
INCREASED PRESSURE OF CSF COMPARTMENT
DECREASED CSF ABSORPTION FROM ARACHNOID VILLI
INCREASED VENOUS PRESSURE IN SAGITAL SINUS AND CNS
DECREASED VENOUS DRAINAGE FROM CSF DECREASED VENOUS DRAINAGE OF THE LUMBAR PLEXUS AND YUGULAR VEINS
Methods After institutional review board approval and following Health Insurance Portability and Accountability guidelines, we conducted a prospective, observational study involving patients selected for elective bariatric surgery. Between 2017 and 2019, all patients undergoing sleeve gastrectomy to treat severe obesity were enrolled in this study and had several parameters tested, as explained below. Exclusion criteria were age <18 years, pre-existing renal failure, and failure to provide written, informed consent, as indicated in the Declaration of Helsinki. Our a priori hypothesis was that hemodynamic changes observed during acute elevations of IAP are triggered by intracranial hypertension and the Cushing reflex, mediated by release of vasopressin (see Fig 1). To assess this hypothesis, we identified 4 different stages during which we would measure the following 6 parameters: (1) IAP, (2) intrathoracic pressure, (3) ONSD as an indirect sign of ICP, (4) vasopressin levels in blood, (5) urine osmolality, and (6) urine output. These measurements were performed at different levels of pneumoperitoneal and intrathoracic pressure, after gaining intravenous access, with the patient anesthetized and ventilated via an endotracheal tube, in a supine position, and after a Foley
INCREASED INTRACRANIAL PRESSURE CSF EFFECT
ARTERIAL CEREBROVASCULAR DILATATION
VQ MISMATCH COMPRESSION OF OF LOWER LOBE OF THE LUNGS
INCREASED INTRATHORACIC PRESSURE
VENOUS EFFECT INFERIOR VENA CAVA COMPRESSION
abdominal compartment syndrome. A second endpoint of this study was to investigate any correlation between acutely elevated ICP and the hemodynamic response that might be elicited by a Cushing reflex mediated by vasopressin release, affecting urine osmolality and urine output.
VASOPRESSIN RELEASE ARTERIAL EFFECT INCREASED CARDIAC PRELOAD AND EJECTION FRACTION
DECREASED URINE OUTPUT
HYPERCARBIA
PERITONEAL ABSORPTION OF CO2
INCREASED CEREBRAL PERFUSION PRESSURE CO2 H30
INCREASED IAP CRANIAL DISPLACEMENT DIAPHRAGM
Fig 1. Cushing reflex mediated by release of vasopressin during acute elevations of IAP. CSF, cerebrospinal fluid; VQ, ventilation-perfusion.
L. Montorfano et al. / Surgery xxx (2019) 1e6
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Table I Vasopressin and osmolality changes after acute elevation of IAP N ¼ 16
Baseline*
Pneumoperitoneumy
z
PEEPx
k
Vasopressin pg/mL Serum osmolality mosm/kg Urine osmolality mosm/kg
2.37 ± 5.23 353.13 ± 192.12 605.47 ± 220.2
45.48 ± 16.83 289.33 ± 7.31 527.6 ± 246.5
.0001 .1605 .0291
54.75 ± 16.18 290.56 ± 2.56 539.86 ± 222.1
.0001 .1625 .0121
P value
P value
END¶ 31.57 ± 18.04 326.60 ± 145.81 493.1 ± 213.64
Data are presented as mean ± standard deviation. * Baseline ¼ with no pneumoperitoneum. y Pneumoperitoneum ¼ 10e15 min after insufflation of the pneumoperitoneum with CO2 to 15 mmHg intraabdominal pressure, with PEEP at 5 cmH2O. z P value for baseline versus pneumoperitoneum. x PEEP ¼ 10e15 min after stabilization of PEEP at 10 cmH2O, with the pneumoperitoneum still at 15 mmHg. k P value for baseline versus PEEP. ¶ END ¼ 10e15 min after complete desufflation of the pneumoperitoneum, at basal mechanical ventilation.
catheter was in place in the urinary bladder. The 4 different stages were as follows: (1) Stage 1: baseline, with no pneumoperitoneum; (2) Stage 2: 10 to 15 minutes after insufflation of the pneumoperitoneum with CO2 to 15 mmHg IAP, with positive endexpiratory pressure (PEEP) at 5 cm H2O; (3) Stage 3: 10 to 15 minutes after stabilization of PEEP at 10 cm H2O, with the pneumoperitoneum still at 15 mmHg; (4) Stage 4: 10 to 15 minutes after complete desufflation of the pneumoperitoneum, at basal mechanical ventilation. The measurements included these 6 parameters: (1) IAP: assessed via a laparoscopic insufflator with highpressure nozzles directing CO2 into the cannula until the desired IAP of 15 mmHg (standard for all laparoscopic procedures) is achieved. The laparoscopic insufflator has a continuous flow circuit that is activated and evacuates intraabdominal gas, recirculating and detecting minor changes in IAP in real time, adjusting the flow, either by insufflating more gas into the abdominal cavity or venting it out of the access port to keep the IAP stable. (2) Intrathoracic pressure: indirectly measured by PEEP on a General Electric Aisys Ventilator (General Electric, Boston, MA) that delivers oxygen and anesthetic gases to the patient and removes CO2, providing controlled mechanical ventilation. A #7.0 (female patients) or #8.0 (male patients) Shiley Cuffed Basic Endotracheal Tube (Medtronic, Minneapolis, MN) d a latex-free, soft flexible polyvinyl chloride tube d was used for this study. (3) Urine collection: through a Foley catheter from the beginning of surgery to postoperative Day 1. Urine osmolality was assessed at set time points and hourly urine output was measured for at least 24 hours to evaluate expected significant variations even after the procedure ends, since renal adaptation could take longer.
(4) Serum/plasma collection: blood draws to evaluate specific values of plasma vasopressin (anti-diuretic hormone) and serum osmolality. (5) Mean arterial pressure (MAP): non-invasive standard monitoring during anesthesia (6) PEEP: Anesthesiologists routinely adapt PEEP to maintain optimal ventilation, especially in obese patients and during laparoscopic procedures ONSD: a 7.5-MHz linear ultrasound probe was used to measure the diameter of the optic nerve sheath, 3 mm behind the globe; with 1 trained study personnel (MD), supervised by the anesthesiologist, taking noninvasive sonographic pictures. The ONSD was measured from each captured picture and the measurement was recorded in the patient’s chart. The ONSD was measured before pneumoperitoneum (base line measurement, 0 minute), at 15 and 30 minutes, and after deflation. Normal ONSD was estimated to be less than 4.5 mm based on previous literature. Higher values (4.5 mm) are considered abnormal. We considered each patient his/her own control to evaluate ONSDs during the different stages of
Statistical analysis For our power analysis, our expectation was that we would observe a 20% to 25% increase in the normal value of vasopressin versus baseline. We also made the following assumptions: That the normal range value of vasopressin is from 1 to 4 pg/mL. According to the number stated in the reference articles, we assumed a coefficient of variation of 0.455. A type I error rate for the overall test comparing the 3 groups of 0.05. That data would be normally distributed. Power, b ¼ 80%. Repeated measures analysis of variance was used to compare mean levels of vasopressin across the 4 different conditions, with
Table II Changes in MAP and ONSD after acute elevation of IAP N ¼ 16
Baseline*
Pneumoperitoneumy
P valuez
PEEPx
P valuek
END¶
MAP (mmHg) ONSD left ONSD right
80.38 ± 21.0 0.37 ± 0.04 0.37 ± 0.05
93.0 ± 14.3 0.44 ± 0.04 0.44 ± 0.00
.021 .0003 .0018
90.56 ± 15.1 0.49 ± 0.16 0.53 ± 0.18
.1652 .0079 .0035
89.69 ± 21.8 0.34 ± 0.04 0.37 ± 0.038
Data are presented as mean ± standard deviation. * Baseline ¼ with no pneumoperitoneum. y Pneumoperitoneum ¼ 10e15 min after insufflation of the pneumoperitoneum with CO2 to 15 mmHg IAP, with PEEP at 5 cmH2O; x PEEP ¼ 10e15 min after stabilization of PEEP at 10 cmH2O, with the pneumoperitoneum still at 15 mmHg. ¶ END ¼ 10e15 min after complete desufflation of the pneumoperitoneum at basal mechanical ventilation. z P value for baseline versus pneumoperitoneum. k P value for baseline versus PEEP Mean ± standard deviation.
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reading (Fig 2). Meanwhile, the ONSD, reflective of ICP, rose and fell in parallel with the rise and fall in vasopressin, averaging abovenormal levels in both the right and left eyes during Stage 3 (Fig 3). Discussion
Fig 2. Changes in serum vasopressin with pneumoperitoneum. Baseline ¼ with no pneumoperitoneum; Pneumoperitoneum ¼ 10e15 min after insufflation of the pneumoperitoneum with CO2 to 15 mmHg IAP, with PEEP at 5 cmH2O; PEEP ¼ 10e15 minutes after stabilization of PEEP at 10 cmH2O, with the pneumoperitoneum still at 15 mmHg; END ¼ 10e15 minutes after complete desufflation of the pneumoperitoneum, at basal mechanical ventilation.
comparisons between any 2 conditions assessed using paired t tests. All tests were 2-tailed. Results A total of 16 patients were enrolled at the time of the analysis. Of these, 11 were female and 5 were male. Mean patient age was 45.0 ± 10.0 years. The mean preoperative body mass index was 41.1 (±4.4) kg/ m2. All 16 (100%) laparoscopic procedures were sleeve gastrectomies. MAP and serum osmolality did not exhibit any statistically significant change when measured across the 4 data-collection points during the intervention. On the other hand, a significant reduction in urine osmolality was observed (P ¼ .03 and P ¼ .01 at Stages 2 and 3, relative to baseline) (Tables I and II). Serum vasopressin was 50-fold higher than baseline when measured during pneumoperitoneum (P < .001 for both Stages 2 and 3, relative to baseline), with 56% (n ¼ 9) of patients having a vasopressin level >65pg/mL when measured at an elevated PEEP. This level remained significantly elevated, relative to baseline, throughout the procedure, albeit trending downward at the Stage 4
Fig 3. Changes in ONSD with pneumoperitoneum. Baseline ¼ with no pneumoperitoneum; Pneumoperitoneum ¼ 10e15 minutes after insufflation of the pneumoperitoneum with CO2 to 15 mmHg IAP, with PEEP at 5 cmH2O; PEEP ¼ 10e15 minutes after stabilization of PEEP at 10 cmH2O, with the pneumoperitoneum still at 15 mmHg; END ¼ 10e15 minutes after complete desufflation of the pneumoperitoneum, at basal mechanical ventilation.
The side effects of acute and prolonged elevations in IAP during CO2 pneumoperitoneum or abdominal compartment syndrome have been the subject of extensive research.4,5,7e10,14,17 In previous studies, we demonstrated that the OSND, measured with ultrasound, will enlarge after establishing acute elevations of IAP while creating a CO2 pneumoperitoneum.12,13 Two mechanisms have been postulated that could explain the correlation between elevations in IAP and ICP. An early mechanical or venous stage is explained as compression of the inferior vena cava via elevation and cranial displacement of the diaphragm caused by the insufflation of the pneumoperitoneum, which reduces venous drainage from the lumbar plexus and central nervous system, thereby increasing the pressure within the brain and spinal canal.7,18 A late chemical or arterial mechanism is related to CO2 diffusion through the peritoneal membrane into the arterial vasculature, which results in an increase in PaCO2 and reflex vasodilation in the central nervous system (CNS) that leads to an increase in ICP, following the Monroe-Kellie hypothesis.5,6 The effects of elevated ICP on renal hemodynamics have been studied under experimental and clinical settings, though they remain incompletely understood.12,16 Decreased cardiac output and increased vascular and renal resistance have been proposed as mechanisms underlying the sudden impairment of renal function following increases in IAP, though correcting cardiac output has not been found to restore normal renal function.19 Placing ureteral stents to counteract high pressure compression on ureters also has failed to restore normal urine output.4 Catecholamines and vasopressin release have been proposed to play an important role in this mechanism.4,13e15,20 Two studies on this topic have been conducted with the aim of identifying significant antidiuretic hormone changes during laparoscopy and its positional changes.13,21 Both studies showed a variable but nonsignificant increase in plasma vasopressin concentration after insufflation causing pneumoperitoneum. What could have been in the past an obstacle to better explain the hemodynamic response to acute elevations in ICP was the measurement of the ICP itself, since it was only feasible by invasive transcranial techniques. Lately, however, several studies have validated the use of optic nerve ultrasound as a noninvasive, accurate, safe, reproducible, and cost-effective tool for assessing ICP, reducing potentially harmful consequences of invasive transcranial measurements.12,15,16 In our study, the ONSD increased drastically (over 20-fold) when pneumoperitoneum was established and during the elevated PEEP phase. Along with this, it was expected that urine output would decrease and urine osmolality increase. This is because the renal filtration gradient is the mechanical force across the glomerulus and equals the difference between the glomerular filtration pressure and the proximal tubular pressure. In the presence of intra-abdominal hypertension, proximal tubular pressure may be assumed equal to IAP; thus, the glomerular filtration pressure can be estimated as the MAP minus 2 times the IAP. Thus, changes in the IAP will have a greater impact upon renal function and urine production than those caused by changes in MAP.14,18,19,22,23 As a result, increased urine osmolarity would be expected to be one of the first visible signs of intra-abdominal hypertension. In our series, urine osmolality decreased. The reason for this is unclear but may be multifactorial. To begin with, all of our patients were obese, and the majority were morbidly obese, and obesity, in itself, has been shown to cause chronic kidney disease that could have altered the kidneys’ ability to concentrate urine.24 In addition, the vast majority of our patients had diabetes mellitus, and their
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serum glucose levels may have spiked during the stress of surgery, causing urine to dilute. Another potential explanation is fluid overload from anesthesia upon induction. In our patients, serum vasopressin was more than 20-fold higher than baseline when measured during pneumoperitoneum and 56% (n ¼ 9) of patients had a vasopressin level >65 pg/mL when measured at an elevated PEEP. As observed in other similar clinical scenarios like intracranial bleeding, when there is an acute elevation of ICP, the Cushing reflex is activated via the release of vasopressin, which is done to increase cardiac preload and ejection fractions, thereby maintaining cerebral blood flow.7,9,10,21,25,26 This latter finding supports our hypothesis that the oliguric response observed in abdominal compartment syndrome might be the result of the acute elevation in IAP that, in turn, triggers increased intrathoracic pressure resulting in decreased venous outflow from the CNS via the lumbar and jugular veins, which in turn results in acute elevations of ICP that could create cerebral ischemia. To prevent the abovementioned insult, the CNS, by means of a Cushing reflex, will release vasopressin to mobilize venous blood and augment the preload, which will increase the ejection fraction and maintain cerebral blood flow (see Fig 1). The reason that vasopressin levels remain high is related to the arterial or chemical phase of ICP, in turn related to the continued cerebrovascular dilatation triggered by the hypercarbia that results from the absorption of peritoneal CO2. The latter will require a longer period of time to return to normal values, dependent upon the patient’s ventilation status and level of sedation. This study is, to our knowledge, the first literature report to analyze the mechanisms of action and to attempt to explain the oligo-anuric response to abdominal compartment syndrome that is triggered by elevated ICP and released vasopressin. We further hypothesize that, by administering vasopressin antagonists, renal impairment and acute kidney injury might be prevented, as has already been shown in a rat model.22 Our study has several weaknesses. Among them is that ours is a small patient population of nonrandomized patients; as such, we cannot rule out random error or bias in our results. A larger patient population would have provided us with more powerful statistical analysis to document causative effects. Another weakness related to the small number of subjects is that we did not adjust for multiple comparisons; this said, the fall in urine osmolality was our only positive finding that would have failed to satisfy a Bonferroniadjusted significance threshold of P .008. Third, all of our patients were obese (most morbidly obese, with a mean body mass index of approximately 41 kg/m2) and most likely had diabetes, hypertension, or both, related to their obesity; as such, the current findings would need to be reproduced in other nonobese populations to verify their general applicability. Fourth, likely related to obesity, diabetes, or both and as explained earlier, we observed a decrease rather than the expected increase in urine osmolality in the presence of elevated vasopressin. Fifth, it is possible that insufflation using CO2 might have increased arterial paCO2 and that this, in turn, might have altered ICP. Unfortunately, the use of an inert gas like helium has not yet been approved for use for pneumoperitoneum at our hospital. Finally, although our data are strongly suggestive of a Cushing effect, more definitive proof of this effect would have been to administer some form of vasopressor blockade. This was not part of normal intraoperative care, however, and could have posed some risk to patients. In conclusion, Harvey Cushing is attributed with having established neurosurgery as a surgical subspecialty and, over more than 2,000 brain tumor operations, to have reduced neurosurgical mortality from 50% to only 8%.27 He also described, almost 120 years ago, Cushing’s reflex. In our series of 16 obese patients undergoing sleeve gastrectomies, we found that a Cushing’s reflexlike response might also be at play in patients with abdominal
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compartment syndrome. Specifically, acute elevations in IAP, observed during laparoscopic procedures triggered by CO2 pneumoperitoneum, appeared to increase intrathoracic pressure and elevate PEEP, resulting in an acute elevation of ICP, manifested as enlarged ONSD. Such increases in IAP may increase ICP without altering cerebral perfusion pressure. The latter might be responsible for a Cushing reflex-type response mediated by acute elevations in serum vasopressin levels. Additional studies are underway with more patients to confirm these findings and explain them further. Funding/Support The authors have no funding disclosures to report. Conflict of interest/Disclosure The authors have no conflicts of interest to report. Acknowledgments The authors have no acknowledgments to report. References 1. Cushing H. Concerning a definite regulatory mechanism of the vaso-motor center which controls blood pressure during cerebral compression. Bull Johns Hopkins Hosp. 1901;12:290e292. 2. Beiner JM, Olgivy CS, DuBois AB. Cerebral blood flow changes in response to elevated intracranial pressure in rabbits and bluefish: a comparative study. Comp Biochem Physiol A Physiol. 1997;116:245e252. 3. Leyssens K, Mortelmans T, Menovsky T, Abramowicz D, Twickler MTB, Van Gaal L. The Cushing reflex: Oliguria as a reflection of an elevated intracranial pressure. Case Rep Nephrol. 2017;2017:2582509. 4. Papavramidis TS, Marinis AD, Pliakos I, Kesisoglou I, Papavramidou N. Abdominal compartment syndrome - intra-abdominal hypertension: Defining, diagnosing, and managing. J Emerg Trauma Shock. 2011;4:279e291. 5. Ben-Haim M, Mandeli J, Friedman RL, Rosenthal RJ. Mechanisms of systemic hypertension during acute elevation of intraabdominal pressure. J Surg Res. 2000;91:101e105. 6. Kamine TH, Elmadhun NY, Kasper EM, Papavassiliou E, Schneider BE. Abdominal insufflation for laparoscopy increases intracranial and intrathoracic pressure in human subjects. Surg Endosc. 2016;30:4029e4032. 7. Rosenthal RJ, Hiatt JR, Phillips EH, Hewitt W, Demetriou AA, Grode M. Intracranial pressure. Effects of pneumoperitoneum in a large-animal model. Surg Endosc. 1997;11:376e380. 8. Rosenthal RJ, Friedman RL, Phillipa EH. Intra-abdominal pressure, intracranial pressure, and hemodynamics: a central nervous system-regulated response. In: Rosenthal RJ, Friedman RL, Phillipa EH, eds. The Pathophysiology of Pneumoperitoneum. Berlin: Springer; 1998:85e98. 9. Rosenthal RJ, Friedman RL, Kahn AM, et al. Reasons for intracranial hypertension and hemodynamic instability during acute elevations of intra-abdominal pressure: observations in a large animal model. J Gastrointest Surg. 1998;2:415e425. 10. Rosin D, Rosenthal RJ. Adverse hemodynamic effects of intraabdominal pressure-is it all in the head? Int J Surg Investig. 2001;2:335e345. 11. Mann C, Boccara G, Pouzeratte Y, et al. The relationship among carbon dioxide pneumoperitoneum, vasopressin release, and hemodynamic changes. Anesth Analg. 1999;89:278e283. 12. Dip F, Nguyen D, Rosales A, et al. Impact of controlled intraabdominal pressure on the optic nerve sheath diameter during laparoscopic procedures. Surg Endosc. 2016;30:44e49. 13. Dip F, Nguyen D, Sasson M, Lo Menzo E, Szomstein S, Rosenthal R. The relationship between intracranial pressure and obesity: an ultrasonographic evaluation of the optic nerve. Surg Endosc. 2016;30:2321e2325. 14. Rosin D, Brasesco O, Varela J, et al. Low-pressure laparoscopy may ameliorate intracranial hypertension and renal hypoperfusion. J Laparoendosc Adv Surg Tech A. 2002;12:15e19. 15. Rajajee V, Vanaman M, Fletcher JJ, Jacobs TL. Optic nerve ultrasound for the detection of raised intracranial pressure. Neurocrit Care. 2011;15: 506e515. 16. Kimberly HH, Shah S, Marill K, Noble V. Correlation of optic nerve sheath diameter with direct measurement of intracranial pressure. Acad Emerg Med. 2008;15:201e204. 17. Viinamki O, Punnonen R. Vasopressin release during laparoscopy: role of increased intra-abdominal pressure. Lancet. 1982;1:175e176. 18. Lindberg F, Bergqvist D, Bjorck M, Rasmussen I. Renal hemodynamics during carbon dioxide pneumoperitoneum: an experimental study in pigs. Surg Endosc. 2003;17:480e484.
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19. Harman PK, Kron IL, McLachlan HD, Freedlender AE, Nolan SP. Elevated intraabdominal pressure and renal function. Ann Surg. 1982;196:594e597. 20. Rajajee V, Thyagarajan P, Rajagopalan RE. Optic nerve ultrasonography for detection of raised intracranial pressure when invasive monitoring is unavailable. Neurol India. 2010;58:812e813. 21. Fuchs EC, Forni C. The influence of secondary midbrain lesions and of the Cushing reflex relative to the prognosis of patients in traumatology (e.g. the epidural hematoma). J Neurosurg Sci. 1974;18:26e31. 22. Dolgor B, Kitano S, Yoshida T, Bandoh T, Ninomiya K, Matsumoto T. Vasopressin antagonist improves renal function in a rat model of pneumoperitoneum. J Surg Res. 1998;79:109e114. 23. Gudmundsson FF, Gislason HG, Myking OL, Viste A, Grong K, Svanes K. Hormonal changes related to reduced renal blood flow and low urine output
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under prolonged increased intra-abdominal pressure in pigs. Eur J Surg. 2002;168:178e186. Funes DR, Blanco DG, Gomez CO, et al. Metabolic surgery reduces the risk of progression from chronic kidney disease to kidney failure. Ann Surg. 2019;279: 511e518. Fassot C, Lambert G, Elghozi JL, Lambert E. Impact of the renin-angiotensin system on cerebral perfusion following subarachnoid haemorrhage in the rat. J Physiol. 2001;535:533e540. Widmayer MA, Browning JL, Gopinath SP, Robertson CS, Baskin DS. Increased intracranial pressure is associated with elevated cerebrospinal fluid ADH levels in closed-head injury. Neurol Res. 2010;32:1021e1026. Black PM. Harvey Cushing at the Peter Bent Brigham Hospital. Neurosurgery. 1999;45:990e1001.