Author's Accepted Manuscript
Biochemical Markers of Acute Limb Ischemia, Rhabdomyolysis, and Impact on Limb Salvage J. Devin B. Watson MD, Shaun Gifford MD, W. Darrin Clouse MD, FACS
www.elsevier.com/locate/enganabound
PII: DOI: Reference:
S0895-7967(15)00008-3 http://dx.doi.org/10.1053/j.semvascsurg.2015.01.007 YSVAS50455
To appear in: ĆSemin Vasc Surg
Cite this article as: J. Devin B. Watson MD, Shaun Gifford MD, W. Darrin Clouse MD, FACS, Biochemical Markers of Acute Limb Ischemia, Rhabdomyolysis, and Impact on Limb Salvage, ĆSemin Vasc Surg , http://dx. doi.org/10.1053/j.semvascsurg.2015.01.007 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Seminars in Vascular Surgery – June/Sept Issue Biomarkers in Vascular Surgery
Biochemical Markers of Acute Limb Ischemia, Rhabdomyolysis, and Impact on Limb Salvage
J. Devin B. Watson, MD1; Shaun Gifford, MD1; W. Darrin Clouse, MD, FACS2
1
San Antonio Military Medical Center Division of Vascular Surgery and
2
The Massachusetts General Hospital, Division of Vascular and Endovascular Surgery, Harvard Medical School
Correspondence:
W. Darrin Clouse, MD FACS RPVI Division of Vascular and Endovascular Surgery Massachusetts General Hospital 15 Parkman Street WACC #440 Boston, MA 02114-3117 Office: (617) 726-3567 Fax: (617) 726-8230 [email protected]
Disclaimer: The opinions or assertions contained herein are the private views of the author(s) and are not to be construed as official or as reflecting the views of the Department of the Air Force, the Department of the Army, or the Department of Defense.
ABSTRACT Biochemical markers of ischemia reperfusion injury have been of interest to vascular surgeons and researchers for many years. Acute limb ischemia (ALI) is the quintessential clinical scenario where these markers would seem relevant. The use of biomarkers to preoperatively or perioperatively predict which patients will not tolerate limb salvage efforts or who will have poor functional outcomes following salvage are of immense interest. Creatinine phosphokinase (CK), myoglobin, lactate, LDH, potassium, bicarbonate, and neutrophil/leukocyte ratios are a few of the studied biomarkers available. Currently, the most well studied aspect of ischemia reperfusion injury (IRI) is rhabdomyolysis leading to acute kidney injury. The last ten years have seen significant progression and improvement in treatment of rhabdomyolysis from minor supportive care to use of continuous renal replacement therapy. Identification of specific biomarkers with predictive outcome characteristics in the setting of ischemia reperfusion injury will help guide therapeutic development and potentially mitigate pathophysiologic changes in ALI, including rhabomyolysis. These may further lead to not only improvement in short- and long-term surgical outcomes and limb salvage, but better understanding of the timing and selection of intervention.
Introduction Ischemia reperfusion injury (IRI) is a well-recognized clinical entity with a wide range of impact across nearly all organ systems, which significantly affects the practice of surgeons, anesthesiologist, and intensivists alike. Reperfusion of ischemic tissues carries with it a significant physiologic debt that contributes to systemic complications such as cardiac depression, acute lung injury, renal failure, and poorer limb-related functional outcomes. The primary interest in IRI in the context of ALI and limb salvage surrounds potential serum marker identifiers of severity, and then therapies to reduce this physiologic debt, making IRI a modifiable factor. Thus, this could improve morbidity and mortality associated with lower limb revascularization. From a large body of research generated from both large and small animal studies there are numerous biomarkers associated with ischemia reperfusion injury. For this review we will focus primarily on creatinine phosphokinase (CK), myoglobin, lactate, LDH, potassium, bicarbonate, and neutrophil/leukocyte ratios. Currently there is no one, specific biomarker that portends the attendant morbidity of IRI in the context of lower extremity ischemia. The traits of such a specific biomarker include a rapidly available test obtained expeditiously at the onset of care, which continues to be available throughout all arenas of care and is cheap and ubiquitously available. Information regarding the level and trends of the biomarkers and their predictive value on outcome is the key to their usefulness. Currently few human clinical trials exist to validate usefulness of various markers of limb ischemia and reperfusion. The most widely studied marker of IRI is CK in the process of rhabdomyolysis. The goal of this paper is to define ischemia reperfusion injury
in the context of limb ischemia and review the various serum biomarkers available to the practicing vascular surgeon that enables him or her to anticipate complications with the hope of employing therapies to reduce morbidity and mortality. Ischemia and Reperfusion injury general overview: While IRI is often discussed as one specific clinical entity, it is necessary to understand the underlying pathophysiologic components separately- ischemic injury followed by reperfusion injury. A complete discussion of the various mechanisms and pathways are far outside the scope of this article; however general mechanisms will be briefly discussed. During the ischemia injury phase, skeletal muscles cells exist in an anaerobic environment with significant reduction in aerobic metabolism and oxidative phosphorylation. With the decrease in aerobic respiration, there is inhibition of the NA/K ATPase receptors leading to intracellular calcium (Ca2+) influx triggering a cascade of cellular processes ultimately producing cellular death and leakage of myoglobin, urate, potassium and phosphate into the systemic circulation, see Fig 1.1 During the anaerobic respiration period there are increases in intracellular lactate levels that may or may not be reflected in the circulating serum level of lactic acid due to the degree of ischemic compromise. Additionally, during the ischemic injury phase, water, calcium and sodium leak from the extracellular space into the muscle cells leading to intravascular volume depletion and cellular edema. The increasing cellular edema of muscle cells may further compromise tissue perfusion in the form of compartment syndrome which leads to a vicious cycle of worsening tissue malperfusion.1
During the reperfusion phase of injury, injured cells revert back to aerobic respiration with large demands for ATP production. The hallmark of the reperfusion injury phase is the increase in formation of free radicals which act as potent oxidizing and reducing agents damaging cellular membrane integrity by lipid peroxidation and initiation of apoptotic and cellular necrosis pathways via mitochondrial injury.1,2 Lipid peroxidation occurs further activates the cyclooxygenase and lipoxygenase pathways leading to additional lipid peroxidation and cell membrane damage. In all, this leads to molecular promotion of inflammatory cytokine production and the release of muscle cell contents including electrolytes and acids, enzymes such as LDH, AST, ALT and CPK, and structural components such as myoglobin. Reperfusion also allows for the recruitment of activated neutrophils, which further release a host of inflammatory autocrine and paracrine signals leading to endothelial disruption further compromising tissue perfusion see Fig 1. In the context of acute ischemia and reperfusion of an extremity, all of the above events occur. Additionally, there is a washout of myoglobin, urate, potassium, phosphate, lactate, calcium, hydrogen ions into the systemic circulation that can lead to significant intraoperative or immediate perioperative complications such as worsening local edema, acute renal failure, tachyarrhythmia, myocardial depression, and hemodynamic collapse. Any intervention to modulate or limit the negative impact of these molecules could be useful. Myoglobin, Creatinine Kinase, and the current therapies for Rhabdomyolysis: Haimovici first described the phenomena of acute renal failure with myoglobinuria following revascularization for acute limb ischemia in 1960.3 Muscle
ischemia followed by reperfusion leads to significant myocyte release of myoglobin (Mb) as well as creatinine kinase (CK), which are both surrogates for muscle damage due to ischemia. As such, serum Mb and CK elevations are associated with the development of rhabdomyolysis reflecting the degree of muscle injury and death from IRI. It must be noted that myoglobin is the metabolite directly responsible for acute kidney injury (AKI). Mb kidney injury occurs through Mb deposition in the distal tubules causing tubular obstruction as well as direct nephrotoxicity through liposomal peroxidation, and inflammation in the setting of aciduria.4,5 Mb elimination is generally not affected by glomerular filtration rates as urinary clearance rates are low in both patients with renal failure as well as those with preserved renal function and MB levels peak faster than CK all make it an ideal maker in the vascular surgery patient population.6,7 Serum myoglobin levels >300nmol/L are considered a level when therapeutic interventions should be undertaken. While low urinary Mb clearance in the setting of rhabdomyolysis was previously thought to predict acute renal failure, the Lappalainen et al study suggests that urine Mb clearance does not predict patients who will progress to acute renal failure.6 While Mb is perhaps the more intuitive marker of skeletal ischemia in the setting of ALI and rhabdomyolysis, CK is the biomarker most frequently followed when diagnosing and treating rhabdomyolysis-induced acute kidney injury due to the ubiquitous availability in clinical laboratories and suggestion that CK is a more sensitive indicator of muscle damage.8 Rhabdomyolsis is generally defined by serum CK levels of greater than 5000 Units/L, though clinically significant rhabdomyolysis-induced AKI more commonly occurs in the setting of CK levels of 10 000-15 000 Units/L. Lappalainen et al suggested that CK is a relatively late peaking biomarker when
examined in the context of rhabdomyolysis making it a better marker of ischemia, but not necessarily a marker of AKI, as there is no definite CK level predictive of developing renal failure.6 In the spectrum of limb ischemia, CK and Mb elevation is seldom seen in patients with chronic limb ischemia, likely due in part to ischemic preconditioning and collateral development.7 However, elevated admission plasma CK levels have been shown to be predictive of major amputation in the setting of acute limb ischemia.9 Currie et al of Edinburg and Aberdeen, Scotland demonstrated in a retrospective study of 97 patients presenting with ALI that increased serum CK conferred 56.2% risk of amputation (95% CI, 39.1-73.4%) versus a 4.6% risk of major amputation in the setting of a normal CK. Perhaps the most interesting and clinically relevant finding of the Curie study was that creatinine kinase levels elevated ten times the normal level (2500 Units/L) was nearly 100% predictive of amputation (n=5). The study was limited in that all results were examined at initial inpatient admission and the long-term results of the success or failure of limb salvage in the setting of elevated CK was not defined. While there is no specifically defined level of CK that is indicative of acute limb ischemia, in a study of postoperative cardiac patients developing acute limb ischemia, a CK level of 17 000 U/L was predictive of ALI.10 In the same study, a CK level >5000 U/L carried a 33% mortality risk similar to previous studies.10,11 In light of these observations, clinicians must evaluate for CK elevation, trend levels throughout care, prepare to intervene if initial levels are elevated or continue to rise, and inform patients of the associated risks of elevated levels.
No studies exist examining the outcomes of vascular patients who develop rhabdomyolysis in the setting of reperfusion after ALI. The VA Study Groups demonstrated that dialysis dependent patients carried higher risk of having a major amputation in the setting of revascularization for acute ischemia.12 The question remains does pre- or postoperative CK levels predict in-hospital mortality, morbidity, amputationfree, or graft-related survival specifically. The treatment of rhabdomyolysis and myoglobinuria remains an ongoing and evolving topic. Volume repletion via crystalloid resuscitation remains the principle mainstay of therapy. The benefit of alkalinization of urine using sodium bicarbonate solution and the use of mannitol versus simple volume repletion remains unclear.13,14 The theoretic goal is to prevent precipitation of myoglobin within renal tubules, which occurs in an acidic environment. Brown et al evaluated 2083 trauma ICU patients with elevated CK (>5000 U/L) and found that bicarbonate and mannitol administration did not prevent renal failure, dialysis, or mortality. Other modalities to alkalinize the urine, like acetazolamide, have been suggested in case reports to assist in increasing urine pH, but no solid data or consensus recommendations for use exist. The use of continuous renal replacement therapy (CRRT) as a treatment for rhabdomyolysis has been of particular interest. There is suggestion that CRRT results in significant decreases in serum myoglobin with improvements in serum creatinine, blood urea nitrogen, and potassium levels though current studies do not have the statistical power to demonstrate improvements in mortality compared to standard therapy.15,16 It remains a treatment of last resort in deteriorating patients, thus placing the possible benefit at odds with both a selection and treatment bias.
Neutrophil/Lymphocyte ratio as a marker of Ischemia As described earlier, ischemic injury leads to significant neutrophil activation that further exacerbates IRI. The neutrophil-lymphocyte ratio (NLR) is an inexpensive, ubiquitous test that reflects systemic inflammation. Originally investigated as a prognostic indicator in cancer, NLR also predicts survival in the setting of myocardial ischemia and cardiac procedures.17,18 There has recently been increased interest in utilizing NLR as a prognostic indicator for ALI in the vascular literature. Multiple studies have recently concluded NLR > 5 is associated with higher mortality rates in the setting of critical limb ischemia.19,20 Both studies of NLR assessing survival demonstrated nearly doubling of mortality with an NLR >5 and 5.25, respectively. Chan and colleagues retrospectively evaluated NLR in the setting of infrapopliteal percutaneous interventions for ALI and their findings further corroborated the mounting evidence that NLR >5.25 is associated with higher mortality. However, in those with elevated NLR there was no significant difference in vessel patency compared to the NLR group 5.2 had a 23% amputation rate versus 8% amputation rate in patients with NLR
Biochemical Markers of Acute Limb Ischemia, Rhabdomyolysis, and Impact on Limb Salvage J. Devin B. Watson MD, Shaun Gifford MD, W. Darrin Clouse MD, FACS
www.elsevier.com/locate/enganabound
PII: DOI: Reference:
S0895-7967(15)00008-3 http://dx.doi.org/10.1053/j.semvascsurg.2015.01.007 YSVAS50455
To appear in: ĆSemin Vasc Surg
Cite this article as: J. Devin B. Watson MD, Shaun Gifford MD, W. Darrin Clouse MD, FACS, Biochemical Markers of Acute Limb Ischemia, Rhabdomyolysis, and Impact on Limb Salvage, ĆSemin Vasc Surg , http://dx. doi.org/10.1053/j.semvascsurg.2015.01.007 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Seminars in Vascular Surgery – June/Sept Issue Biomarkers in Vascular Surgery
Biochemical Markers of Acute Limb Ischemia, Rhabdomyolysis, and Impact on Limb Salvage
J. Devin B. Watson, MD1; Shaun Gifford, MD1; W. Darrin Clouse, MD, FACS2
1
San Antonio Military Medical Center Division of Vascular Surgery and
2
The Massachusetts General Hospital, Division of Vascular and Endovascular Surgery, Harvard Medical School
Correspondence:
W. Darrin Clouse, MD FACS RPVI Division of Vascular and Endovascular Surgery Massachusetts General Hospital 15 Parkman Street WACC #440 Boston, MA 02114-3117 Office: (617) 726-3567 Fax: (617) 726-8230 [email protected]
Disclaimer: The opinions or assertions contained herein are the private views of the author(s) and are not to be construed as official or as reflecting the views of the Department of the Air Force, the Department of the Army, or the Department of Defense.
ABSTRACT Biochemical markers of ischemia reperfusion injury have been of interest to vascular surgeons and researchers for many years. Acute limb ischemia (ALI) is the quintessential clinical scenario where these markers would seem relevant. The use of biomarkers to preoperatively or perioperatively predict which patients will not tolerate limb salvage efforts or who will have poor functional outcomes following salvage are of immense interest. Creatinine phosphokinase (CK), myoglobin, lactate, LDH, potassium, bicarbonate, and neutrophil/leukocyte ratios are a few of the studied biomarkers available. Currently, the most well studied aspect of ischemia reperfusion injury (IRI) is rhabdomyolysis leading to acute kidney injury. The last ten years have seen significant progression and improvement in treatment of rhabdomyolysis from minor supportive care to use of continuous renal replacement therapy. Identification of specific biomarkers with predictive outcome characteristics in the setting of ischemia reperfusion injury will help guide therapeutic development and potentially mitigate pathophysiologic changes in ALI, including rhabomyolysis. These may further lead to not only improvement in short- and long-term surgical outcomes and limb salvage, but better understanding of the timing and selection of intervention.
Introduction Ischemia reperfusion injury (IRI) is a well-recognized clinical entity with a wide range of impact across nearly all organ systems, which significantly affects the practice of surgeons, anesthesiologist, and intensivists alike. Reperfusion of ischemic tissues carries with it a significant physiologic debt that contributes to systemic complications such as cardiac depression, acute lung injury, renal failure, and poorer limb-related functional outcomes. The primary interest in IRI in the context of ALI and limb salvage surrounds potential serum marker identifiers of severity, and then therapies to reduce this physiologic debt, making IRI a modifiable factor. Thus, this could improve morbidity and mortality associated with lower limb revascularization. From a large body of research generated from both large and small animal studies there are numerous biomarkers associated with ischemia reperfusion injury. For this review we will focus primarily on creatinine phosphokinase (CK), myoglobin, lactate, LDH, potassium, bicarbonate, and neutrophil/leukocyte ratios. Currently there is no one, specific biomarker that portends the attendant morbidity of IRI in the context of lower extremity ischemia. The traits of such a specific biomarker include a rapidly available test obtained expeditiously at the onset of care, which continues to be available throughout all arenas of care and is cheap and ubiquitously available. Information regarding the level and trends of the biomarkers and their predictive value on outcome is the key to their usefulness. Currently few human clinical trials exist to validate usefulness of various markers of limb ischemia and reperfusion. The most widely studied marker of IRI is CK in the process of rhabdomyolysis. The goal of this paper is to define ischemia reperfusion injury
in the context of limb ischemia and review the various serum biomarkers available to the practicing vascular surgeon that enables him or her to anticipate complications with the hope of employing therapies to reduce morbidity and mortality. Ischemia and Reperfusion injury general overview: While IRI is often discussed as one specific clinical entity, it is necessary to understand the underlying pathophysiologic components separately- ischemic injury followed by reperfusion injury. A complete discussion of the various mechanisms and pathways are far outside the scope of this article; however general mechanisms will be briefly discussed. During the ischemia injury phase, skeletal muscles cells exist in an anaerobic environment with significant reduction in aerobic metabolism and oxidative phosphorylation. With the decrease in aerobic respiration, there is inhibition of the NA/K ATPase receptors leading to intracellular calcium (Ca2+) influx triggering a cascade of cellular processes ultimately producing cellular death and leakage of myoglobin, urate, potassium and phosphate into the systemic circulation, see Fig 1.1 During the anaerobic respiration period there are increases in intracellular lactate levels that may or may not be reflected in the circulating serum level of lactic acid due to the degree of ischemic compromise. Additionally, during the ischemic injury phase, water, calcium and sodium leak from the extracellular space into the muscle cells leading to intravascular volume depletion and cellular edema. The increasing cellular edema of muscle cells may further compromise tissue perfusion in the form of compartment syndrome which leads to a vicious cycle of worsening tissue malperfusion.1
During the reperfusion phase of injury, injured cells revert back to aerobic respiration with large demands for ATP production. The hallmark of the reperfusion injury phase is the increase in formation of free radicals which act as potent oxidizing and reducing agents damaging cellular membrane integrity by lipid peroxidation and initiation of apoptotic and cellular necrosis pathways via mitochondrial injury.1,2 Lipid peroxidation occurs further activates the cyclooxygenase and lipoxygenase pathways leading to additional lipid peroxidation and cell membrane damage. In all, this leads to molecular promotion of inflammatory cytokine production and the release of muscle cell contents including electrolytes and acids, enzymes such as LDH, AST, ALT and CPK, and structural components such as myoglobin. Reperfusion also allows for the recruitment of activated neutrophils, which further release a host of inflammatory autocrine and paracrine signals leading to endothelial disruption further compromising tissue perfusion see Fig 1. In the context of acute ischemia and reperfusion of an extremity, all of the above events occur. Additionally, there is a washout of myoglobin, urate, potassium, phosphate, lactate, calcium, hydrogen ions into the systemic circulation that can lead to significant intraoperative or immediate perioperative complications such as worsening local edema, acute renal failure, tachyarrhythmia, myocardial depression, and hemodynamic collapse. Any intervention to modulate or limit the negative impact of these molecules could be useful. Myoglobin, Creatinine Kinase, and the current therapies for Rhabdomyolysis: Haimovici first described the phenomena of acute renal failure with myoglobinuria following revascularization for acute limb ischemia in 1960.3 Muscle
ischemia followed by reperfusion leads to significant myocyte release of myoglobin (Mb) as well as creatinine kinase (CK), which are both surrogates for muscle damage due to ischemia. As such, serum Mb and CK elevations are associated with the development of rhabdomyolysis reflecting the degree of muscle injury and death from IRI. It must be noted that myoglobin is the metabolite directly responsible for acute kidney injury (AKI). Mb kidney injury occurs through Mb deposition in the distal tubules causing tubular obstruction as well as direct nephrotoxicity through liposomal peroxidation, and inflammation in the setting of aciduria.4,5 Mb elimination is generally not affected by glomerular filtration rates as urinary clearance rates are low in both patients with renal failure as well as those with preserved renal function and MB levels peak faster than CK all make it an ideal maker in the vascular surgery patient population.6,7 Serum myoglobin levels >300nmol/L are considered a level when therapeutic interventions should be undertaken. While low urinary Mb clearance in the setting of rhabdomyolysis was previously thought to predict acute renal failure, the Lappalainen et al study suggests that urine Mb clearance does not predict patients who will progress to acute renal failure.6 While Mb is perhaps the more intuitive marker of skeletal ischemia in the setting of ALI and rhabdomyolysis, CK is the biomarker most frequently followed when diagnosing and treating rhabdomyolysis-induced acute kidney injury due to the ubiquitous availability in clinical laboratories and suggestion that CK is a more sensitive indicator of muscle damage.8 Rhabdomyolsis is generally defined by serum CK levels of greater than 5000 Units/L, though clinically significant rhabdomyolysis-induced AKI more commonly occurs in the setting of CK levels of 10 000-15 000 Units/L. Lappalainen et al suggested that CK is a relatively late peaking biomarker when
examined in the context of rhabdomyolysis making it a better marker of ischemia, but not necessarily a marker of AKI, as there is no definite CK level predictive of developing renal failure.6 In the spectrum of limb ischemia, CK and Mb elevation is seldom seen in patients with chronic limb ischemia, likely due in part to ischemic preconditioning and collateral development.7 However, elevated admission plasma CK levels have been shown to be predictive of major amputation in the setting of acute limb ischemia.9 Currie et al of Edinburg and Aberdeen, Scotland demonstrated in a retrospective study of 97 patients presenting with ALI that increased serum CK conferred 56.2% risk of amputation (95% CI, 39.1-73.4%) versus a 4.6% risk of major amputation in the setting of a normal CK. Perhaps the most interesting and clinically relevant finding of the Curie study was that creatinine kinase levels elevated ten times the normal level (2500 Units/L) was nearly 100% predictive of amputation (n=5). The study was limited in that all results were examined at initial inpatient admission and the long-term results of the success or failure of limb salvage in the setting of elevated CK was not defined. While there is no specifically defined level of CK that is indicative of acute limb ischemia, in a study of postoperative cardiac patients developing acute limb ischemia, a CK level of 17 000 U/L was predictive of ALI.10 In the same study, a CK level >5000 U/L carried a 33% mortality risk similar to previous studies.10,11 In light of these observations, clinicians must evaluate for CK elevation, trend levels throughout care, prepare to intervene if initial levels are elevated or continue to rise, and inform patients of the associated risks of elevated levels.
No studies exist examining the outcomes of vascular patients who develop rhabdomyolysis in the setting of reperfusion after ALI. The VA Study Groups demonstrated that dialysis dependent patients carried higher risk of having a major amputation in the setting of revascularization for acute ischemia.12 The question remains does pre- or postoperative CK levels predict in-hospital mortality, morbidity, amputationfree, or graft-related survival specifically. The treatment of rhabdomyolysis and myoglobinuria remains an ongoing and evolving topic. Volume repletion via crystalloid resuscitation remains the principle mainstay of therapy. The benefit of alkalinization of urine using sodium bicarbonate solution and the use of mannitol versus simple volume repletion remains unclear.13,14 The theoretic goal is to prevent precipitation of myoglobin within renal tubules, which occurs in an acidic environment. Brown et al evaluated 2083 trauma ICU patients with elevated CK (>5000 U/L) and found that bicarbonate and mannitol administration did not prevent renal failure, dialysis, or mortality. Other modalities to alkalinize the urine, like acetazolamide, have been suggested in case reports to assist in increasing urine pH, but no solid data or consensus recommendations for use exist. The use of continuous renal replacement therapy (CRRT) as a treatment for rhabdomyolysis has been of particular interest. There is suggestion that CRRT results in significant decreases in serum myoglobin with improvements in serum creatinine, blood urea nitrogen, and potassium levels though current studies do not have the statistical power to demonstrate improvements in mortality compared to standard therapy.15,16 It remains a treatment of last resort in deteriorating patients, thus placing the possible benefit at odds with both a selection and treatment bias.
Neutrophil/Lymphocyte ratio as a marker of Ischemia As described earlier, ischemic injury leads to significant neutrophil activation that further exacerbates IRI. The neutrophil-lymphocyte ratio (NLR) is an inexpensive, ubiquitous test that reflects systemic inflammation. Originally investigated as a prognostic indicator in cancer, NLR also predicts survival in the setting of myocardial ischemia and cardiac procedures.17,18 There has recently been increased interest in utilizing NLR as a prognostic indicator for ALI in the vascular literature. Multiple studies have recently concluded NLR > 5 is associated with higher mortality rates in the setting of critical limb ischemia.19,20 Both studies of NLR assessing survival demonstrated nearly doubling of mortality with an NLR >5 and 5.25, respectively. Chan and colleagues retrospectively evaluated NLR in the setting of infrapopliteal percutaneous interventions for ALI and their findings further corroborated the mounting evidence that NLR >5.25 is associated with higher mortality. However, in those with elevated NLR there was no significant difference in vessel patency compared to the NLR group 5.2 had a 23% amputation rate versus 8% amputation rate in patients with NLR
