If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Address reprint requests to: Stephanie Franzén, MSc, PhD, Department of Surgical Sciences, Anesthesiology and Intensive Care, Uppsala University, Uppsala University Hospital, Entrance 70, 1st floor, 751 85, Uppsala, Sweden
Approximately 7% of patients undergoing non-cardiac surgery with general anesthesia develop postoperative acute kidney injury (AKI). It is well-known that general anesthesia may have an impact on renal function and water balance regulation, but the mechanisms and potential differences between anesthetics are not yet completely clear.
Recently published large animal studies have demonstrated that volatile (gas) anesthesia stimulates the renal sympathetic nervous system more than intravenous propofol anesthesia, resulting in decreased water and sodium excretion and reduced renal perfusion and oxygenation. Whether this is the case also in humans remains to be clarified. Increased renal sympathetic nerve activity may impair renal excretory function and oxygenation and induce structural injury in ischemic AKI models and could therefore be a contributing factor to AKI in the perioperative setting. This review summarizes anesthetic agents’ effects on the renal sympathetic nervous system that may be important in the pathogenesis of perioperative AKI.
General anesthesia is a key component in modern perioperative care. It is defined as controlled and reversible unconsciousness with analgesia, amnesia, and muscle paralysis that enables invasive mechanical ventilation and surgical procedures.
Practice Guidelines for Moderate Procedural Sedation and Analgesia 2018: A Report by the American Society of Anesthesiologists Task Force on Moderate Procedural Sedation and Analgesia, the American Association of Oral and Maxillofacial Surgeons, American College of Radiology, American Dental Association, American Society of Dentist Anesthesiologists, and Society of Interventional Radiology.
Although anesthesia has developed into a generally safe procedure, it remains associated with risks. Acute kidney injury (AKI) is a common postoperative complication affecting approximately 7% of patients undergoing non-cardiac surgery
AKI is defined by a rapid decrease in urine output or glomerular filtration rate (GFR), where the latter is reflected by an increase in plasma creatinine concentration within seven days of the insult.
A retrospective cohort summarized that the incidence of postoperative AKI in hospitalized patients was 18% and that AKI was associated with an increase in mortality.
Another study showed that of the patients who developed AKI (with no known preexisting kidney disease), 18% had developed chronic kidney disease at a one-year follow up.
The causes of perioperative AKI are several. Hemodynamic alterations by anesthesia or events such as surgically induced hemorrhage are likely central in the pathogenesis. The incidence of postoperative AKI has been directly associated with intraoperative hypotension, which supports this hypothesis.
Relationship between intraoperative mean arterial pressure and clinical outcomes after noncardiac surgery: toward an empirical definition of hypotension.
Renal blood flow (RBF) is kept more or less constant despite changes in arterial blood pressure (RBF autoregulation), as long as the pressure is within normal physiological limits.
Pre-treatment with the angiotensin receptor 1 blocker losartan protects renal blood flow and oxygen delivery after propofol-induced hypotension in pigs.
Relationship between intraoperative mean arterial pressure and clinical outcomes after noncardiac surgery: toward an empirical definition of hypotension.
It remains unclear how RBF and the autoregulatory threshold in humans is affected by anesthesia, but it is likely that major reductions in arterial blood pressure significantly impair RBF. Systemic hypotension also unloads arterial baroreceptors, which will cause a reflexive increase in sympathetic nervous activity and activation of the renin-angiotensin-aldosterone system (RAAS).
Ultimately, this results in vasoconstriction, including the renal vascular bed, which may restore systemic blood pressure and GFR, but at the risk of further reducing RBF.
Perioperative AKI is also believed to potentially be a consequence of the surgical insult, perhaps via inflammatory mechanisms.
The type of surgery appears to have a significant impact, with major abdominal and cardiac surgeries having the highest incidence of postoperative AKI.
It has been concluded that mechanical ventilation can cause AKI through various mechanisms, including inflammatory crosstalk between the lungs and kidneys and positive pressure ventilation, which reduces venous return and cardiac output. Also, mechanical ventilation has been associated with increased activation of the RAAS and a decrease in atrial and brain natriuretic peptides, which would result in increased renal sodium and water retention.
The choice of anesthetic agent may also affect the incidence of postoperative AKI. For example, it has been demonstrated that volatile gas anesthesia results in higher incidence of postoperative AKI during colorectal surgery, nephrectomy, spinal surgery, and overall non-cardiac surgery compared with intravenous propofol anesthesia (Table 1).
Comparison of the impact of propofol versus sevoflurane on early postoperative recovery in living donors after laparoscopic donor nephrectomy: a prospective randomized controlled study.
Propofol intravenous anaesthesia with desflurane compared with desflurane alone on postoperative liver function after living-donor liver transplantation: A randomised controlled trial.
Effect of sevoflurane-based or propofol-based anaesthesia on the incidence of postoperative acute kidney injury: A retrospective propensity score-matched analysis.
Moreover, another recently published retrospective study reported that there was no significant difference in postoperative AKI incidence between different volatile anesthetics (isoflurane, desflurane, sevoflurane).
A large systematic review assessed anesthetic effects on postoperative complications by comparing regional anesthesia (spinal or epidural neuraxial blockade) with general anesthesia.
The authors reported that postoperative AKI incidence was lower in patients who had spinal or epidural anesthesia than in patients who were anesthetized with any type of general anesthetic modality. Lastly, intraoperative oliguria (urine output < 0.5 ml kg−1 h−1) has in some surgical settings been demonstrated to be a significant predictor of postoperative AKI.
This implies that anesthesia could affect renal excretory function without actually resulting in structural damage to the kidney or later renal impairment, which makes it more complicated to predict renal function based on changes in urine output during anesthesia.
Table 1Acute Kidney Injury During Different Anesthesia in Humans
Effect of sevoflurane-based or propofol-based anaesthesia on the incidence of postoperative acute kidney injury: A retrospective propensity score-matched analysis.
Propofol intravenous anaesthesia with desflurane compared with desflurane alone on postoperative liver function after living-donor liver transplantation: A randomised controlled trial.
Comparison of the impact of propofol versus sevoflurane on early postoperative recovery in living donors after laparoscopic donor nephrectomy: a prospective randomized controlled study.
A summary of clinical trials comparing AKI incidence when various anesthetic agents have been used in different surgical settings. AKI – acute kidney injury; AKIN – Acute Kidney Injury Network; eGFR – estimated glomerular filtration rate; KDIGO – Kidney Disease, Improving Global Outcome; NA – not applicable; TCI/TIVA – target controlled infusion/total intravenous anesthesia; UO – urine output.
After induction, anesthesia may be maintained with continuous infusion of propofol (or other intravenous anesthetic) or an inhaled volatile agent together with an appropriate analgesic (often an opioid). Sevoflurane and other halogenated ethers (such as isoflurane and desflurane) are inhalational volatile gases that are also commonly used for general anesthesia, in both patients and experimental animal models for research. They stimulate GABAA receptors whose main ligand, γ-aminobutyric acid (GABA), is the most important inhibitory neurotransmitter in the central nervous system (Fig. 1).
Figure 1Hypothetical overview of volatile anesthesia and the effects in the central nervous system with yellow indications on how the response might be increased or decreased by the volatile agent. Volatile anesthesia exerts its actions through GABAA agonism, which could inhibit the GABAergic signaling pathways in the MO, thus reducing SNA to all organs from the RVLM. However, studies have showed that volatile anesthesia independently increases RSNA ultimately increasing renal vasoconstriction and renal sodium and water retention.
Hypothetically, this could be the result of another central pathway regulating RSNA independently of the MO. Studies have shown that i.c.v. Na+ and AngII sensed by the CVO regulates the PVN and that the PVN can directly regulate RSNA.
Comparison between the effects on hemodynamic responses of central and peripheral infusions of hypertonic NaCl during hemorrhage in conscious and isoflurane-anesthetized sheep.
Hence, volatile agents might interfere with the PVN independently which could be one explanation for the paradoxical finding that volatile anesthesia increases RSNA but not overall SNA (green dashed line). AngII – angiotensin II; CVO – circumventricular organs; DVN – dorsal vagal nucleus; GABAA – gamma aminobutyric acid type A; HR – heart rate; i.c.v. – intracerebroventricular; MO – medulla oblongata; N. vagus – vagus nerve; NTS – nucleus tractus solitarii; NA – nucleus ambiguus; PVN – paraventricular nucleus; RSNA – renal sympathetic nerve activity; RVLM – rostral ventrolateral medulla; SNA – sympathetic nerve activity. (Vecteezy.com was used to render anatomical vectors.) (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Volatile gases are associated with high levels of inorganic fluoride and sevoflurane contributes to the production of compound A; both these substances have been found to cause nephrotoxicity in animal models.
Detailed cardiovascular effects of volatile anesthetics have been reviewed previously. Both isoflurane and sevoflurane are associated with decreased cardiac output, vascular resistance, and cardiac contractility in a dose-dependent fashion. Overall, SNA is also reduced by these anesthetics.
Moreover, the arterial baroreceptor reflex is dose-dependently less sensitive during isoflurane, sevoflurane, and desflurane anesthesia than in the conscious state. Interestingly, although volatile gases are associated with suppression of overall SNA, isoflurane and sevoflurane have been shown to selectively increase renal sympathetic nerve activity (RSNA).
The kidneys have both efferent and afferent nerves. Efferent renal nerves convey information from the neuroaxis to the kidneys (RSNA). They consist of post-ganglionic sympathetic fibers which exert their action via release of the neurotransmitter norepinephrine (NE), which binds to post-synaptic adrenoceptors. Increased RSNA results in: (a) renal vasoconstriction with decreased RBF and GFR and increased renal vascular resistance; (b) increased renin release from juxtaglomerular granular cells; (c) increased renal tubular water and sodium reabsorption in all renal tubular segments (Fig. 2).
Studies have also shown that renal denervation causes decreased sodium and water reabsorption in the proximal tubules, the loop of Henle, and the distal tubules, and that stimulation of the renal nerves results in increased sodium and water reabsorption in the proximal tubules and increased sodium and chloride reabsorption in the loop of Henle.
Figure 2Schematic overview of the potential role of efferent RSNA in the pathogenesis of AKI. Volatile anesthesia increases efferent RSNA in numerous animal models.
Dose-dependent increases in the renal sympathetic nerve activity during rapid increase in isoflurane concentration in intact, lower airway-deafferented, and baroreceptor-deafferented rabbits.
This likely results in an increase in afferent renal sensory nerve activity, but it is unknown if this feedback mechanism will be inhibitory or excitatory on efferent RSNA. Efferent RSNA exerts its effects through three primary mechanisms (orange): 1) increased tubular sodium and water retention by increased activity of the Na/K-ATPase and the Na/H exchanger; 2) increased renin release by the juxtaglomerular cells; 3) renal vasoconstriction. These physiological responses will stimulate the production of angiotensin II and aldosterone (grey), which will further contribute to tubular sodium and water retention and renal vasoconstriction.
It has not been verified that efferent RSNA is elevated by volatile anesthesia and causes renal vasoconstriction in humans. However, if this is the case, as seen in sheep (25–30% reduction in RBF), it could be of concern in patients with chronic kidney disease, diabetes, or cardiovascular disease. Ultimately, these three main effects of efferent RSNA (orange) modulate the variables used for classifying AKI (green): urine output and GFR. AKI – acute kidney injury; AngI – angiotensin I; AngII – angiotensin II; GFR – glomerular filtration rate; RAAS – renin angiotensin aldosterone system; RSNA – renal sympathetic nerve activity. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Afferent renal nerve fibers convey information from renal sensory mechanoreceptors and chemoreceptors to the neuroaxis. In the normal kidney, increases in afferent renal sensory nerve activity result in decreased efferent RSNA (Fig. 3). This negative feedback mechanism constitutes an inhibitory reno-renal reflex mechanism. However, in pathological situations, such as AKI, stimulation of afferent renal nerve activity results in increases in both RSNA and sympathetic nerve activity to other organs, thus creating excitatory reno-renal and reno-systemic effects.
How general anesthesia with volatile agents affects these feedback mechanisms in humans remains unknown (Fig. 3), yet some studies have demonstrated that isoflurane anesthesia blunts the reno-renal and reno-systemic effects of increased renal pelvic pressure and capsaicin in rats.
This suggests that volatile anesthesia might independently decrease the sensitivity of the afferent nerves.
Figure 3Schematic overview of the efferent RSNA and afferent renal sensory nerve activity feedback system on the reno-renal and reno-systemic axis in normal and pathophysiological settings, and during volatile anesthesia. Left: During normal physiological conditions, an increase in efferent RSNA results in increased renal sensory nerve activity, which has an inhibitory effect on efferent RSNA and on sympathetic nerve activity to other organs. Center: Under pathophysiological conditions, the inhibitory mechanism of afferent sensory nerve activity is modulated to instead have an excitatory effect on both efferent RSNA and sympathetic nerve activity to other organs.
As RSNA is a crucial regulator of renal functions, with significant impact, it is important to measure. In experimental settings, RSNA can be measured by mounting the renal nerves with recording electrodes.
In situ, the release of renin and renal spillover of NE are often used to assess changes in RSNA. However, if these responses are used as proxies for RSNA, it is critical to exclude any other factors that may affect them. For example, renin release can be increased by reductions in renal perfusion pressure or sodium chloride load at the macula densa. Another method to analyze and interpret the effects of RSNA is renal denervation. Abolition of a functional response in the kidney following renal denervation indicates dependence on intact renal innervation (i.e., RSNA). Renal denervation has been demonstrated to prevent the development of renal injury in different settings,
and has been shown to be a relevant treatment for drug-resistant human hypertension, with beneficial results confirmed in multiple controlled clinical trials.
In the 1980s, volatile anesthesia was shown to have attenuating effects on the arterial baroreceptor reflex, which was believed to contribute to the decrease in sympathetic tone seen during anesthesia.
However, unlike all other volatile agents, desflurane is associated with increased muscle SNA, which seems independent of baroreceptor unloading and can be attenuated by propofol.
It was reported that RSNA was increased by numerous volatile agents (isoflurane, desflurane, and enflurane) at low concentrations, whereas high concentrations caused a reduction in blood pressure and RSNA.
Importantly, the sheep anesthetized with propofol in that study did not have increased RSNA. This is in accordance with other reports where propofol, opioids, and dexmedetomidine have been shown to have central sympathoinhibitory properties on vasculature, skin, and subcutaneous and stellate ganglion activity.
Isoflurane anesthesia also decreased RBF, oxygen delivery, and regional renal perfusion compared with in the conscious state and more than propofol anesthesia. Moreover, systemic hemodynamics were similar between the two anesthetic modalities, suggesting that the effect on renal function is independent of systemic hemodynamics such as arterial pressure, cardiac output, and vascular resistance. In accordance with this, it has been demonstrated that sheep sedated with sevoflurane have increased RSNA compared with in the conscious state.
The animals had impaired renal excretory function, where both urine output and sodium excretion were significantly reduced during sevoflurane anesthesia. The authors also tested if this response could be abolished by renal denervation. Sheep with intact renal nerves had decreased RBF, urine output, and sodium excretion when subjected to sevoflurane anesthesia. In denervated sheep, this effect was abolished. This indicates that RSNA was the major contributor to the reduced renal function by sevoflurane anesthesia in this sheep model. Furthermore, angiotensin II and vasopressin inhibitors did not contribute with a significant effect on diuresis during sevoflurane anesthesia, suggesting that RSNA could be the major mechanism of oliguria during volatile anesthesia.
How volatile agents might differentially affect the sympathetic nervous system across organs remains poorly investigated and it is not entirely clear through what mechanism volatile anesthetics stimulate RSNA. The effect of isoflurane on RSNA has been studied in intact rabbits and compared with either low- or high-pressure baroreceptor-deafferented rabbits.
Dose-dependent increases in the renal sympathetic nerve activity during rapid increase in isoflurane concentration in intact, lower airway-deafferented, and baroreceptor-deafferented rabbits.
The study showed that RSNA was increased in all settings, but the increase was smallest in the high-pressure baroreceptor-deafferented rabbits. This suggests that isoflurane-induced RSNA is to some degree dependent on high-pressure baroreceptors, but that cerebral stimulatory pathways of volatile anesthesia may also be involved. Another study in dogs showed that low concentrations of various volatile agents increased RSNA via somatosympathetic A delta and C fibers, whereas higher concentrations suppressed RSNA.
Specific actions of halothane, isoflurane, and desflurane on sympathetic activity and A delta and C somatosympathetic reflexes recorded in renal nerves in dogs.
Therefore, it seems likely that the effects on RSNA from volatile anesthetics are dose-dependent. Also, as numerous animal models demonstrate a renal sympathoexcitatory effect of volatile agents, this effect might not be entirely species-dependent. Cerebral activation of sympathetic pathways to different organs might be differentiated based on the stimulus (hypotension, hemorrhage, osmolality, etc.), which could be one explanation for the paradoxical finding that RSNA is increased by volatile anesthesia, while overall SNA is decreased (Fig. 1). The differences in regulation of cardiac SNA and RSNA have been demonstrated in both conscious and anesthetized animals. The diverse response in cardiac and renal SNA was demonstrated in hemorrhaged sheep, where intravenous hypertonic saline resuscitation increased cardiac, but not renal, SNA.
The role of the paraventricular nucleus of the hypothalamus in the regulation of cardiac and renal sympathetic nerve activity in conscious normal and heart failure sheep.
Comparison between the effects on hemodynamic responses of central and peripheral infusions of hypertonic NaCl during hemorrhage in conscious and isoflurane-anesthetized sheep.
Interestingly, this study showed that isoflurane anesthesia abolished the protective effects of intracerebroventricular hypertonic saline, but only slightly reduced the effects of intravenous hypertonic saline. Therefore, the authors suggested that anesthesia per se might interfere with and block the central autonomic reflex cardiovascular control. Furthermore, while increased sodium osmolality causes a central inhibition of renin release,
isoflurane anesthesia blunted this effect in this study, suggesting that isoflurane independently induces renin release via RSNA. Angiotensin II has cerebral effects similar to those of hypertonic saline.
Intravenous hypertonic NaCl acts via cerebral sodium-sensitive and angiotensinergic mechanisms to improve cardiac function in haemorrhaged conscious sheep.
It has been demonstrated that the protective effects of intracarotid angiotensin II infusion during hemorrhage (similar to those of hypertonic saline) were reduced during isoflurane anesthesia compared with in conscious animals.
Taken together, these studies clearly indicate that RSNA might be regulated separately from SNA to other organs. Thus, volatile anesthesia might modulate the cerebral regulatory mechanisms, causing an increase of RSNA that is independent of peripheral stimuli (Fig. 1).
As it is complicated and invasive to measure RSNA during surgical procedures in the operating room, it might be better to use humoral responses as markers for changes in RSNA. A most likely downstream effect of increased RSNA is excess renin release. It has been demonstrated that isoflurane-anesthetized sheep have higher levels of plasma renin than conscious sheep.
Comparison between the effects on hemodynamic responses of central and peripheral infusions of hypertonic NaCl during hemorrhage in conscious and isoflurane-anesthetized sheep.
As it has also been reported that both isoflurane and sevoflurane cause an increase in RSNA in sheep, the reported increase in renin levels during isoflurane anesthesia may be the effect of RSNA. In two clinical trials, plasma renin concentration was used as proxy for RSNA during sevoflurane anesthesia.
Also, plasma levels of renin, but not vasopressin, were higher during sevoflurane anesthesia than when the children were conscious. This is in line with the renal effects of isoflurane and sevoflurane seen in sheep with increased RSNA. Moreover, a clinical trial randomized adults who underwent elective spinal surgery to either propofol or sevoflurane anesthesia.
The sevoflurane-anesthetized patients were oliguric and had reduced sodium excretion and high levels of plasma renin during anesthesia (before surgery). These effects were not seen in patients who underwent propofol anesthesia. Interestingly, all patients in the study had increased levels of vasopressin postoperatively, regardless of anesthetic modality, suggesting that the surgical trauma, not anesthesia per se, is the main trigger of vasopressin release. Though it is not certain that volatile anesthetics stimulate RSNA in humans, the change in renal excretory function is comparable to that seen in sheep where RSNA was recorded. However, even if this is found to be the case in humans, it remains unclear if renal sympathoexcitation is a significant contributor in the pathogenesis of perioperative AKI.
Pathophysiology of Renal Sympathoexcitation in Ischemia-Induced AKI
Renal sympathetic nerve activity is considered to be an important factor in the pathogenesis of short- and long-term renal diseases.
Tissue ischemia produces an intrarenal release of adenosine, which increases both afferent renal sensory nerve activity and efferent RSNA. This ischemia-induced adenosine release may contribute in the pathogenesis of AKI by diminishing the afferent reno-renal reflex suppression of RSNA, thus increasing RSNA even further.
The absence of changes in arterial pressure in the aforementioned studies suggests that reno-systemic reflexes are not activated by ischemia. Renal denervation or RSNA inhibition (through drugs) can attenuate or normalize the ischemia-induced abnormalities in renal hemodynamic and excretory function, renal venous plasma NE concentration, and histological abnormalities (summarized in Table 2).
Furthermore, renal denervation eliminates the contribution of RSNA-induced renal venous NE spillover. Since NE remains present in the systemic circulation, sympathetically innervated non-renal organs must still contribute NE to the systemic circulation. Experiments using centrally acting α-2 adrenoceptor agonists to decrease RSNA provide evidence of the beneficial effects of renal denervation in the ischemia model. Administration of clonidine (α-2 adrenoceptor agonist), agmatine, and moxonidine (α-2 adrenoceptor/imidazole-1 receptor agonists) attenuate the increases in RSNA, serum creatinine concentration, and renal vein plasma NE concentration, and decrease the severity of renal injury (summarized in Table 2).
Moreover, afferent renal sensory nerve activity was found to be protective against ischemia in an experimental rat model. It was shown that ischemia stimulated renal sensory neurons to release calcitonin gene-related peptide, resulting in increased prostaglandin release – thus attenuating the effects of ischemic injury by reducing the inflammatory response.
Efferent RSNA produces effects that contribute to increased renal workload, reduced RBF, and oxygen delivery, which are also key factors in the pathogenesis of AKI. In the hypotensive and hypovolemic setting, RSNA is increased, leading to immediate renal vasoconstriction. This, together with the effects on glomerulotubular function and hormonal changes, contributes to the development of renal ischemia.
Table 2Renal Effects of Sympathoexcitation in Ischemia-Induced AKI
A summary of studies with inhibition or abolishment of RSNA in ischemia-induced AKI. Pathophysiological functions with intact RSNA in each study. AKI – acute kidney injury; BUN – blood urea nitrogen; FENa+ – fractional Na+ excretion; GFR – glomerular filtration rate; i.c.v. – intracerebroventricular; i.v. – intravenous; NE – norepinephrine; P-Cr – plasma creatinine; RSNA – renal sympathetic nerve activity.
Choosing the proper anesthetic modality is imperative in experimental research models, yet inhouse preferences and regulations might reduce the options significantly in both experimental and clinical settings. Isoflurane is a commonly used anesthetic modality in ischemia-induced AKI rodent models.
The studies discussed in this review indicate that anesthesia modulates renal hemodynamics and excretory function compared with in the conscious state. It also appears that volatile anesthesia has a greater impact on these variables than intravenous propofol anesthesia. Isoflurane and sevoflurane are reported to increase RSNA, which produces renal vasoconstriction, decreases RBF and GFR, and increases water and sodium retention.
These changes could cause or aggravate the effects of renal ischemia in AKI models. Sevoflurane has been shown to be protective against ischemia-induced AKI signaling pathways in vitro. However, in that setting, no effects of systemic SNA and RSNA can be accounted for.
Furthermore, a study on rats demonstrated that sevoflurane was more protective of renal function post ischemia-reperfusion compared with pentobarbital or ketamine.
Propofol has also been demonstrated to be reno-protective in ischemia-induced AKI, which seems to be an effect of activated anti-inflammatory pathways, inhibition of proinflammatory pathways, and deactivation of apoptotic pathways.
Anesthesia is an essential component in many experimental in vivo models and cannot be replaced. When working with experimental models where normal renal physiology is expected or necessary, it is important to consider that anesthesia might severely affect renal vascular tone, GFR, or urine output and even contribute to renal ischemia. Different anesthetic modalities could be tested to ensure the independence of anesthetic agents on any study outcome.
The published research on anesthetic effects on renal function in humans is inconclusive. Why some studies show lower AKI incidence after propofol anesthesia compared with volatile anesthesia and some show no difference at all is not readily explained. How controlled the clinical trials are regarding administration of fluids, vasopressors, and comorbidities in the patient populations seems to affect study outcomes. An aspect that also needs to be considered is that most studies use the Kidney Disease Improving Global Outcome standards to assess renal function, yet there are numerous reasons why this classification system might fail as a proxy for renal function during anesthesia. Fluid treatment, age, sex, diet, and muscle mass might complicate the interpretation of plasma creatinine as a marker for AKI.
As discussed, volatile anesthesia may reduce urine output to the degree that the AKI criteria are reached, but it is uncertain how that associates with structural long-term damage to the kidney. Furthermore, oliguria in combination with normal intraoperative fluid resuscitation will result in plasma volume expansion, affecting plasma creatinine concentration.
Since these medications reduce arterial pressure and anesthesia induction also may cause hypotension, continuing antihypertensive medications until surgery is usually discouraged. The rationale is to prevent any hypotensive events, which can independently contribute to AKI. However, the mechanisms through which hypotensive events trigger AKI remain unclear. If it includes effects mediated by angiotensin II (as discussed in this review), discontinuing renin-angiotensin system inhibitors would not be beneficial to the kidneys. Recently published trials have shown that though patients with continued treatment with renin-angiotensin system inhibitors had more frequent intraoperative hypotension events, there was no increased incidence of postoperative AKI.
A Systematic Review of Outcomes Associated With Withholding or Continuing Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers Before Noncardiac Surgery.
We have recently conducted two experimental studies with results indicating that the increased activity of the renin-angiotensin system following propofol-induced hypotension and major hemorrhage mediates renal vasoconstriction, ultimately resulting in renal hypoxia.
Pre-treatment with the angiotensin receptor 1 blocker losartan protects renal blood flow and oxygen delivery after propofol-induced hypotension in pigs.
Thus, the risk for renal ischemia might be even higher during sevoflurane anesthesia (with its independent mechanisms to increase RSNA and plasma renin concentration), but this remains to be investigated.
Although this is not fully investigated, sevoflurane might affect RSNA also in humans. Though RSNA has not been recorded directly, the observed changes in renal function (reduced water and sodium excretion) and increased plasma renin during volatile anesthesia are in line with an increase in RSNA. Furthermore, even if RSNA is increased by volatile anesthesia in humans, it is not clear if this contributes to perioperative AKI. It also remains to be investigated if renal blood flow is reduced by these anesthetics and if continuation of RAAS inhibitors before surgery could actually be beneficial for some patients.
CONCLUSION
The incidence of perioperative AKI remains high and contributes significantly to an increased risk of morbidity and mortality. The volatile anesthetic sevoflurane is associated with an elevated risk of AKI after major abdominal surgery, nephrectomy, and non-cardiac surgery. Volatile anesthesia increases RSNA in numerous animal models, causing renal vasoconstriction, renal sodium and water retention, and renin release. It remains to be investigated in detail how volatile anesthesia affects renal function in humans. A reduction in renal blood flow also in humans would have direct impact on the choice of anesthesia for certain patient groups and types of surgery, since reduced kidney perfusion increases the risk of ischemia-induced AKI. Another key issue is thus if there are any differences in AKI incidence when volatile anesthesia is used compared with other anesthetics, such as propofol. It is also essential to describe how RSNA is increased by volatile anesthesia. Hence, both clinical trials and experimental models are needed to further elucidate the underlying mechanisms of sympathoexcitation involving volatile anesthetics, and if anesthetic modulation of renal nerve activity impacts the incidence of perioperative AKI.
REFERENCES
Practice Guidelines for Moderate Procedural Sedation and Analgesia 2018: A Report by the American Society of Anesthesiologists Task Force on Moderate Procedural Sedation and Analgesia, the American Association of Oral and Maxillofacial Surgeons, American College of Radiology, American Dental Association, American Society of Dentist Anesthesiologists, and Society of Interventional Radiology.
Relationship between intraoperative mean arterial pressure and clinical outcomes after noncardiac surgery: toward an empirical definition of hypotension.
Pre-treatment with the angiotensin receptor 1 blocker losartan protects renal blood flow and oxygen delivery after propofol-induced hypotension in pigs.
Comparison of the impact of propofol versus sevoflurane on early postoperative recovery in living donors after laparoscopic donor nephrectomy: a prospective randomized controlled study.
Propofol intravenous anaesthesia with desflurane compared with desflurane alone on postoperative liver function after living-donor liver transplantation: A randomised controlled trial.
Effect of sevoflurane-based or propofol-based anaesthesia on the incidence of postoperative acute kidney injury: A retrospective propensity score-matched analysis.
Dose-dependent increases in the renal sympathetic nerve activity during rapid increase in isoflurane concentration in intact, lower airway-deafferented, and baroreceptor-deafferented rabbits.
Specific actions of halothane, isoflurane, and desflurane on sympathetic activity and A delta and C somatosympathetic reflexes recorded in renal nerves in dogs.
The role of the paraventricular nucleus of the hypothalamus in the regulation of cardiac and renal sympathetic nerve activity in conscious normal and heart failure sheep.
Comparison between the effects on hemodynamic responses of central and peripheral infusions of hypertonic NaCl during hemorrhage in conscious and isoflurane-anesthetized sheep.
Intravenous hypertonic NaCl acts via cerebral sodium-sensitive and angiotensinergic mechanisms to improve cardiac function in haemorrhaged conscious sheep.
A Systematic Review of Outcomes Associated With Withholding or Continuing Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers Before Noncardiac Surgery.
00065-1&id=gr1.jpg){kind=link}
00065-1&id=gr2.jpg){kind=link}
00065-1&id=gr3.jpg){kind=link}