Introduction
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Traditionally it has been thought that during septic shock, renal blood flow decreases leading to pre-renal kidney injury. This implied that if we could improve the cardiac output and renal blood flow, the kidneys would recover. Recent research challenges these concepts, with interesting therapeutic implications.
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New paradigm of microvascular physiology in renal acute kidney injury
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This is beautifully explained in the following 30-minute lecture by Australian critical care guru Rinaldo Bellomo. If you don't have 30 minutes right now, the key points are summarized below so you can keep reading and watch the video later.
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To summarize briefly, in septic shock renal blood flow is typically normal or increased, despite a reduction in glomerular filtration rate. This may be due to vasodilation of capillaries which bypass the glomerulus combined with vasodilation of efferent arterioles (allowing blood to shunt through the kidney without improving the glomerular filtration rate). It is possible that renal function could be improved by therapies which vasodilate the afferent arteriole or vasoconstrict the efferent arteriole (Bellomo 2014).
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General therapeutic implications of renal microvascular dysfunction
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Generally management of septic shock focuses on the macrovascular level: hemodynamic assessment is followed by interventions to stabilize the mean arterial pressure, cardiac output, etc. Microvascular dysfunction is concerning because it suggests that even if we improve macrovascular physiology, this may still be inadequate to ensure tissue perfusion. However, better understanding of microvascular function may open opportunities to improve renal function.
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Ideally, for any vasopressor or inotrope we would have a complete understanding on its effects on both microvascular and macrovascular physiology. Unfortunately much of this data is not available. The remainder of this post will attempt to examine various ICU therapies from the perspective of the renal microvasculature.
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Avoid nonsteroidal anti-inflammatory drugs (NSAIDs), ACE-inhibitors, and Angiotensin-receptor blockers (ARBs)
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All of these drugs impair the ability of the glomerulus to compensate for hypoperfusion, making them nephrotoxic in the setting of hemodynamic instability. NSAIDs impair the synthesis of renal prostaglandins, whereas ACE-inhibitors and ARBs block the ability of angiotensin II to vasoconstrict the efferent arteriole.
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Avoid hyperchloremic acidosis, typically by using balanced crystalloids
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Hyperchloremic acidosis appears to impair renal perfusion by causing vasoconstriction of the afferent arteriole. This may generally be avoided by the use of balanced crystalloids for resuscitation. For patients with pre-existing hyperchloremic acidosis, it may be reasonable to correct the acidosis. This was explored in detail in the last post.
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Norepinephrine improves renal perfusion and function
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Norepinephrine is currently the front-line vasopressor for septic shock based on studies showing reduced mortality and arrhythmia compared to dopamine (De Backer 2010, 2012). Norepinephrine is effective in restoring adequate blood pressure with subsequent improvements in renal blood flow, urine output, and glomerular filtration rate. Although there has been some concern regarding the possibility of renal vasoconstriction, this does not appear to occur in the setting of septic shock at clinically relevant doses (Bellomo 2008). The early use of norepinephrine to rapidly achieve an adequate mean arterial pressure and avoid renal injury was previously discussed here.
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Low-dose vasopressin may improve renal function
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Theoretically, adjunctive vasopressin is an attractive option to add to norepinephrine. Vasopressin selectively vasoconstricts the efferent arteriole, thereby increasing the glomerular filtration rate. Patients in septic shock have disproportionately low vasopressin levels compared to other forms of shock, suggesting that a relative vasopressin deficiency actually contributes to the pathogenesis of shock and renal microvascular dysfunction (Landry 1997).
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Four prospective randomized controlled trials (RCTs) have provided information about vasopressin in comparison to norepinephrine with regards to renal function in septic shock. Although most current reviews of sepsis focus on the largest study (the VASST study), a better understanding may be obtained by considering all of these RCTs.
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Patel 2002 studied 24 patients with septic shock on an average of 20 mcg/min norepinephrine. Patients were randomized to receive blinded up-titration of either vasopressin (to at most 0.08 units/min) or norepinephrine (to at most 16 mcg/min) over an hour, followed by three hours of observation. Patients in the norepinephrine group had no change in total norepinephrine requirement, urine output, or creatinine clearance. In contrast, patients in the vasopressin group doubled their urine output (p < 0.05) with a significant increase in creatinine clearance (p < 0.05; figure below).
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Lauzier 2006 performed a prospective, open-label, RCT of 23 patients with septic shock. Patients were randomized to receive either vasopressin (0.04-2 units/min) or norepinephrine (0.1-2.8 ug/kg/min). However, 85% of patients in the vasopressin group required norepinephrine at some point to achieve target blood pressure. Patients in the vasopressin group had higher systemic vascular resistance and lower systemic oxygen delivery, but ultimately had less organ dysfunction as measured by SOFA score. Patients treated with norepinephrine maintained a stable creatinine clearance, whereas patients treated with vasopressin on average doubled their creatinine clearance: (table below).
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Morelli 2009 randomized 45 patients with septic shock to fixed-dose infusion of terlipressin (1.3 ug/kg/hr), vasopressin (0.03 U/min) or norepinephrine (15 mcg/min) plus open-label norepinephrine. Patients in the vasopressin group had a stable creatinine whereas patients in the norepinephrine group elevated their creatinine over 48 hours (p < 0.001; table below).
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Morelli 2009 randomized 45 patients with septic shock to fixed-dose infusion of terlipressin (1.3 ug/kg/hr), vasopressin (0.03 U/min) or norepinephrine (15 mcg/min) plus open-label norepinephrine. Patients in the vasopressin group had a stable creatinine whereas patients in the norepinephrine group elevated their creatinine over 48 hours (p < 0.001; table below).
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The VASST trial randomized 778 patients with septic shock to receive open-label norepinephrine plus either 0.01-0.03 U/min vasopressin or 5-15 mcg/min norepinephrine. There was a 5.7% absolute mortality reduction in the vasopressin group which didn't reach statistical significance (p = 0.1). This improvement was restricted to the prospectively defined group of patients with less severe septic shock (defined as initial norepinephrine requirement <15 mcg/min), among whom p = 0.04 (figure below). This post-hoc subgroup analysis is open to multiple interpretations.
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The VASST trial randomized 778 patients with septic shock to receive open-label norepinephrine plus either 0.01-0.03 U/min vasopressin or 5-15 mcg/min norepinephrine. There was a 5.7% absolute mortality reduction in the vasopressin group which didn't reach statistical significance (p = 0.1). This improvement was restricted to the prospectively defined group of patients with less severe septic shock (defined as initial norepinephrine requirement <15 mcg/min), among whom p = 0.04 (figure below). This post-hoc subgroup analysis is open to multiple interpretations.
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Gordon 2010 performed a post-hoc analysis of the VASST trial data. Patients were stratified according to a modified RIFLE categorization of acute kidney injury (table below). Differences in renal outcomes were restricted to patients with mild renal injury initially (“risk” category). Among patients in the risk category, vasopressin reduced both worsening of renal failure and the need for dialysis by about two-fold (p = 0.03 and 0.02, respectively). Interestingly, mortality benefit from vasopressin was also restricted to patients in the risk category (55% vs. 31%, p = 0.01). This post-hoc analysis suggests that vasopressin may be beneficial if started early, prior to the occurrence of significant end-organ damage.
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Overall the results of the VASST trial were disappointing compared to prior RCTs. This may be due to the low dose of vasopressin used (up to 0.03 U/hr) and substantial delays to initiation of vasopressin (average delay of twelve hours). Another possibility is that unlike the other three studies, VASST did not select for patients with normal or elevated cardiac output. It is possible that vasopressin is only beneficial in the subset of patients with normal or elevated cardiac output (i.e., hyperdynamic septic shock). We await the VANISH trialwhich promises to utilize larger doses of vasopressin (up to 0.06 U/hr) with shorter delays to initiation.
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Aside from renal perfusion, another possible advantage of vasopressin is avoiding excessive beta-adrenergic stimulation of the heart. Norepinephrine has been established as superior to dopamine for most applications, due primarily to less intense beta-agonist activity than dopamine (e.g., norepinephrine causes fewer arrhythmias). However, recent research regarding esmolol in septic shock by Morelli 2013 raises the question of whether norepinephrine may also provide excessive beta-agonist activity in some cases. Vasopressin allows reduction of norepinephrine doses, thereby reducing beta-adrenergic stimulation.
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Aside from renal perfusion, another possible advantage of vasopressin is avoiding excessive beta-adrenergic stimulation of the heart. Norepinephrine has been established as superior to dopamine for most applications, due primarily to less intense beta-agonist activity than dopamine (e.g., norepinephrine causes fewer arrhythmias). However, recent research regarding esmolol in septic shock by Morelli 2013 raises the question of whether norepinephrine may also provide excessive beta-agonist activity in some cases. Vasopressin allows reduction of norepinephrine doses, thereby reducing beta-adrenergic stimulation.
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Bottom line? Vasopressin is safe in septic shock, particularly at the very low doses currently recommended (0-0.03 U/min). All four RCTs found that vasopressin improves renal function (although only retrospectively in VASST). There is a possible signal of mortality benefit within the VASST trial. This is an area of equipoise, but currently the risk/benefit ratio seems to favor using vasopressin. Although this is often used as a last-ditch effort in refractory shock, it appears most beneficial in milder shock. Vasopressin could be useful given its catecholamine-sparing properties, particularly among patients with tachycardia or arrhythmia.
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Conclusions
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It is commonly believed that the pathophysiology of renal failure in sepsis is due to hypoperfusion causing “pre-renal” renal failure similar to hypovolemic shock. Unfortunately, septic kidney injury is much more complex than that, involving inflammation and microvascular dysfunction. Septic kidney injury typically occurs despite normal or elevated renal blood flow, with maldistribution of microvascular perfusion. Therefore, treatments which improve cardiac output and renal blood flow (e.g., renal-dose dopamine) will not necessarily help. We are only beginning to understand how various therapies interact with the kidney. Some treatments which show promise in preventing renal injury include:
- Avoidance of NSAIDs, ACE-inhibitors, and angiotensin-receptor blockers.
- Avoidance of hyperchloremic acidosis, typically by using balanced crystalloids for volume resuscitation.
- Support of mean arterial pressure with norepinephrine.
- Adjunctive low-dose vasopressin to maintain glomerular filtration.
This is the second of a series of three posts about preserving renal function in critically ill patients (the first one is here). Stay tuned.
Image credits:
– Kidney anatomy: http://en.wikipedia.org/wiki/Kidney
– Glomerular diagram modified from: http://cbsetextbooks.weebly.com/19-excretory-products-and-their-elimination.html#sthash.9FpOjK0X.dpbs
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I have had patients that I have run a bit higher on Levophed to create a bp closer to 120 sbp and had them begin to make urine on their own. Now it makes more sense why this has worked.
Only 2 out of the 8 patients in the MRI study Bellomo mentions in the video actually had raised CO and renal Q.
Presumably this subset of patients would benefit far more from efferent arteriolar constriction, since they have good supply, but poor glomerular pressure.
It would make sense to divide sepsis-AKI patients into high output or low output groups (using CO as a surrogate for renal Q) and treat the high output group with more vasopressin (?and the low output group with inotropes).
Love this website, thank you for sharing critical care information.