Blood pressure has long been used as a surrogate for tissue perfusion. Although this relationship is clean in the intraoperative period, the same cannot be said for the critically ill patient in the ICU (1 , 2). Recently, more robust associations between hypotension in the critically ill patient and poor outcomes have been suggested, including a need to maintain pressures higher than the traditionally advocated mean arterial pressure of greater than 65 mm Hg (3). However, there are some key concerns while advocating for higher pressures in the ICU. First, there is the trade-off between higher pressures and a potential for worse microcirculatory flow. And second, and probably more importantly, is the difficulty to parse the independent association of an increasing lactate (as an indicator of poor tissue perfusion) and poor outcomes in this patient population. That the combination of low blood pressure and a higher lactate makes for worse outcomes further complicates matters (4). In the absence of a gold standard for tissue perfusion, and the stated fallacies with dependence on blood pressure, serum lactate measurements continue to be used to help understand the flow arm of the flow versus pressure argument.
Lactate levels, although attractive in terms of ease of availability and utility, are not without limitations either. There may be a multitude of reasons where lactate may be elevated in the critically injured patient. Some of these are a direct consequence of hypotension and impaired tissue perfusion and some entirely independent. The first data that suggested poor outcomes with an elevated lactate (more than 4 mmol/L) was published more than 50 years ago (5). Since then, there has been an evolution in the utilization of lactate, and appropriate thresholds have now been described in the critically ill population that qualify for a diagnosis of sepsis (6). However, it would be wrong to consider all causes of elevated lactate to be secondary to sepsis. Lactate elevation may be secondary to several shock states, including any that produce tissue hypoperfusion. Even more important are several subtle masqueraders including liver failure, malignancy, thiamine deficiency, and mitochondrial disease. Of critical importance to the practicing intensivist are drug-induced causes of elevated lactate, some of which may be common components of preexisting pharmacotherapy in the ICU patient (7). Consequently, the clinical diagnosis associated with an elevated lactate should be considered in context of the prognostication and utilization of this value on a laboratory draw. For example, an elevated lactate in the setting of metformin usage on a starving patient, or that in a patient with a diabetic ketoacidosis may be associated with far less mortality and necessitate an entirely different therapeutic approach compared with that in a truly hypo perfused septic hypotensive patient. Since clinical diagnoses almost never clearly declare themselves when a patient presents to the emergency department and gets an elevated lactate on blood work, most initial lactate elevations are treated as septic, with a bolus of fluids and or vasopressors. This, “one-size-fits-all” approach to lactate may have both short- and long-term adverse consequences.
In this issue of Critical Care Medicine, Gleeson et al (8) (Renin as a Marker of Tissue-Perfusion and Prognosis in Critically-Ill Patients [REMARK]-1 investigators) present the results of a single-center, prospective, observational study examining renin levels in critically ill patients without and with circulatory shock from various etiologies. The authors specifically sought to determine associations of renin with continuous renal replacement therapy (CRRT), diurnal changes, and changes associated with drugs affecting renin-angiotensin-aldosterone system (RAAS). Other outcomes included determining the suitability of renin as a marker of tissue perfusion and predictor of mortality in comparison with concurrently drawn lactate levels. The difference of the rate of increase of plasma renin over time in nonsurvivors versus survivors was significantly greater compared with lactate in the same population. Maximum renin appeared to be a much stronger and significant predictor of ICU mortality with an area under the curve for a receiver operator curve (AUC-ROC) of 0.80 (p = 0.04) compared with lactate with an AUC-ROC of 0.70 (p = 0.17). In addition, renin levels were largely unaffected by diurnal variation, CRRT or drugs that were known to influence RAAS.
The discovery of the RAAS dates back to the 1950s and was the culmination of landmark work of two scientific groups across continents. One group was led by Dr. Irvine Page at Cleveland Clinic. This group in Cleveland named it “Angiotonin” and the other led by Dr. Braun Mendez in Argentina named this compound “Hypertensin/Hypertensinogen”. Later on, the two groups agreed on a mutually suitable name of “Angiotensin” and hence was born the RAAS as we know it today (9). The physiology of this axis that works to ensure circulatory balance in normal and disease states is well described. Angiotensinogen is converted to Angiotensin I via secretion of renin, that occurs as a consequence of decreased renal blood flow sensed by the juxtaglomerular apparatus in the kidney nephron. Therefore, a spike in renin secretion would be thought to occur secondary to the mechanisms of hypotension, lack of tissue perfusion, hypoxemia alone or in combination and consequently sympathetic activation that may be the overarching connection across all these states. Although investigation and use of plasma renin levels would seem an attractive alternative to lactate, there are some concerns to its routine use in practice. These, namely diurnal variation in levels, removal via CCRT, and interference by commonly used drugs that cross-talk with RAAS are important in the ICU patient. In this context, the work from the REMARK-1 investigators, showed no diurnal variation, minimal CRRT renin removal, and no significant interaction with RAAS drugs.
At first look, this is a small study, 20 patients and a 112 renin samples. However, the authors were able to power the analysis to 80% and an alpha-error of 0.05 using more than five renin samples per patient for 20 patients. Further, as the authors elute to, the stage of progression of shock at the point of ICU admission and the point of study enrollment was unknown, and this may have influenced peak renin and lactate measurements. Interestingly, the recruited cohort was extremely heterogenous, and while representing a “real world” ICU population, this begs the question of how best to interpret these results. That said, the “non-shock” population in the study by Gleeson et al (8) was one with significant inflammatory insults and some of the mechanisms of insults would overlap, although anaerobic metabolism as a driver of lactate production would be minimal in these. A larger trial with a more homogenous population, for example—only septic shock would be of great interest, and something that the critical care community would be looking at, as the best next step after this “hypothesis generating” set of results that Gleeson et al (8) report. Again, in a purist environment, low blood pressures in the presence of high dose vasopressors would be an important subpopulation. Although the authors report decreasing blood pressure and utilization of high noradrenaline, and higher rate of increase of renin in the nonsurvivor population, the separation of the effect of high dose vasopressors to maintain pressure versus the same pressure without high dose vasopressors seems to be an interesting scientific question for further pursuit as well, in which the effect of these subgroups on renin secretion patterns would need to be examined.
The strengths of the study by Gleeson et al (8) are its novelty, despite the small sample size, since the authors aim to answer a question that will have far-reaching effects on the practice of resuscitation in critical care practice. Recently, the RAAS has been reinvigorated after the resurgence of Angiotensin II as a vasopressor, and work showing potency, efficacy, and safety of this compound in vasodilatory shock (10). The effects of dysfunction of angiotensin-converting enzyme (ACE) levels, secondary to sepsis with or without the concurrent use of enzyme inhibitor pharmacotherapy are not unknown (11). Therefore, renin surges in a hypoperfused state may be a well-established survival mechanism that serves to provide more substrate to ACE and generate more Angiotensin II, which in turn is a potent vasoconstrictor and volume expander via direct and indirect mechanisms. Within the current limitations of lactate previously mentioned, this work provides the bedside clinician an effective and physiologically robust alternative to lactate that may be used as a marker of tissue perfusion. The relationships between lactate and RAAS effecting drugs, and high dose vasopressors were not within the scope of the study by Gleeson et al (8) and again would be fodder for a larger or separate analysis. Of note, the reader should understand that REMARK-1 looks at lactate values at varied and different stages of resuscitation in the involved patient cohort, and this is not the same as the traditionally talked about screening and high values of lactate at greater than 2 mmol/L and greater than 4 mmol/L seen in sepsis resuscitation work from specifically the early phase of resuscitation or admission lactate levels commonly reported. Gleeson et al (8) talk about the phenomenon of “normal” blood lactate levels having a predictive role during these other varied phases of ICU stay as well, and this should serve the reader to understand the precise concept and significance of reported lactate levels in their work (12). It is also important to understand that microcirculation and tissue perfusion are slightly different and renin is not a marker of impaired microcirculation. However, renin may be a better marker of tissue perfusion compared with the currently available standard of care, that is, lactate. Clinical judgment of peripheral perfusion may still be the best method, and there is ongoing work investigating that question (13).
“So, is renin the new lactate?” Maybe not, at least not as yet. The very elegant work done by the REMARK-1 group does show a clear signal to superiority of renin as a marker of mortality. Renin may also be easier to use, not significantly influenced by renal replacement or common drugs that alter the RAAS pathway. There may be thus, less clinical masqueraders of altered renin, compared with altered lactate. However, the population in question was small and heterogenous. In addition, lactate does have a well-established niche as a marker of the success of early resuscitation (14). The work by Gleeson et al (8) does not challenge lactate on that front. However, with a few more well-designed, larger clinical experiments in appropriate populations and at specific stages of resuscitation, renin may well prove itself to be a better, easier to use and physiologically sound marker of tissue perfusion and mortality in the critically ill patient population.
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