Clinical Review

From the Cardiovascular Division, Department of Internal Medicine, University of Minnesota, Minneapolis, MN.

 

Abstract

• Objective: To present a review of cardiorenal syndrome type 1 (CRS1).
• Methods: Review of the literature.
• Results: Acute kidney injury occurs in approximately one-third of patients with acute decompensated heart failure (ADHF) and the resultant condition was named CRS1. A growing body of literature shows CRS1 patients are at high risk for poor outcomes, and thus there is an urgent need to understand the pathophysiology and subsequently develop effective treatments. In this review we discuss prevalence, proposed pathophysiology including hemodynamic and nonhemodynamic factors, prognosticating variables, data for different treatment strategies, and ongoing clinical trials and highlight questions and problems physicians will face moving forward with this common and challenging condition.
• Conclusion: Further research is needed to understand the pathophysiology of this complex clinical entity and to develop effective treatments.

 

Acute decompensated heart failure (ADHF) is an epidemic facing physicians throughout the world. In the United States alone, ADHF accounts for over 1 million hospitalizations annually, with costs in 2012 reaching $30.7 billion [1]. Despite the advances in chronic heart failure management, ADHF continues to be associated with poor outcomes as exemplified by 30-day readmission rates of over 20% and in-hospital mortality rates of 5% to 6%, both of which have not significantly improved over the past 20 years [2,3]. One of the strongest predictors of adverse outcomes in ADHF is renal dysfunction. An analysis from the Acute Decompensated Heart Failure National Registry (ADHERE) revealed the combination of renal dysfunction (creatinine > 2.75 mg/dL and blood urea nitrogen (BUN) > 43 mg/dL) and hypotension (systolic blood pressure (SBP) < 115 mm Hg) upon admission was associated with an in-hospital mortality of > 20% [4]. The Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) registry documented a 16.3% in-hospital mortality when patients had a SBP < 100 mm Hg and creatinine > 2.0 mg/dL at admission [5].

The presence of acute kidney injury in the setting of ADHF is a very common occurrence and was termed cardiorenal syndrome type 1 (CRS1) [6]. The prevalence of CRS1 in single-centered studies ranged from 32% to 40% of all ADHF admissions [7,8]. If this estimate holds true throughout the United States, there would be 320,000 to 400,000 hospitalizations for CRS1 annually, highlighting the magnitude of this problem. Moreover, with the number of patients with heart failure expected to continue to rise, CRS1 will only become more prevalent in the future. In this review we discuss the prevalence, proposed pathophysiology including hemodynamic and nonhemodynamic factors, prognosticating variables, data for different treatment strategies, ongoing clinical trials, and highlight questions and problems physicians will face moving forward in this common and challenging condition.

Pathogenesis of CRS1

Hemodynamic Effects

The early hypothesis for renal dysfunction in ADHF centered on hemodynamics, as reduced cardiac output was believed to decrease renal perfusion. However, analysis of invasive hemodynamics from patients with ADHF suggested that central venous pressure (CVP) was actually a better predictor of the development of CRS1 than cardiac output. In a single-center study conducted at the Cleveland Clinic, hemodynamics from 145 patients with ADHF were evaluated and surprisingly baseline cardiac index was greater in the patients with CRS1 than patients without renal dysfunction (2.0 ± 0.8 L/min/m² vs 1.8 ± 0.4 L/min/m²; P = 0.008). However, baseline CVP was higher in the CRS1 group (18 ± 7 mm Hg vs 12 ± 6 mm Hg; P = 0.001), and there was a heightened risk of developing CRS1 as CVP increased. In fact, 75% of the patients with a CVP of > 24 mm Hg developed renal impairment [9]. In a retrospective study of the Evaluation Study of Congestive Heart Failure and Pulmonary Arterial Catheter Effectiveness (ESCAPE) trial, the only hemodynamic parameter that correlated with baseline creatinine was CVP. However, no invasive measures predicted worsening renal function during hospitalization [10]. Finally, an experiment that used isolated canine kidneys showed increased venous pressure acutely reduced urine production. Interestingly, this relationship was dependent on arterial pressure; as arterial flow decreased smaller increases in CVP were needed to reduce urine output [11]. Together, these data suggest increased CVP plays an important role in CRS1, but imply hemodynamics alone may not fully explain the pathophysiology of CRS1.

Inflammation

As information about how hemodynamics incompletely predict renal dysfunction in ADHF became available, alternative hypotheses were investigated to gain a deeper understanding of the pathophysiology underlying CRS1. A pathological role of inflammation in CRS1 has gained attention due to recent publications. First of all, serum levels of the pro-inflammatory cytokines TNF-a and IL-6 were elevated in patients with CRS1 when compared to health controls [12]. Interestingly, Virzi et al showed that the median value of IL-6 was 5 times higher in CRS1 patients when compared to ADHF patients without renal dysfunction [13]. The negative consequences of elevated serum cytokines were demonstrated when incubation of a human cell line of monocytes with serum from CRS1 patients induced apoptosis in 81% of cells compared to just 11% of cells with control serum [12]. It is possible that cytokine-induced apoptosis could occur in other cell types in different organs in patients with CRS1, which may contribute to both cardiac and renal dysfunction. Finally, analysis from a rat model of CRS1 revealed macrophage infiltration into the kidneys and increased numbers of activated monocytes in the peripheral blood. Interestingly, monocyte/macrophage depletion using liposome clodronate prevented chronic renal dysfunction in the rat model [14]. In summary, these data suggest inflammation contributes to CRS1 pathophysiology, but more experimental data is needed to determine if there is a causal relationship.

Oxidative Stress

Very recently, oxidative stress was proposed to play a role in CRS1. Virzi et al analyzed serum levels of markers of oxidative stress and compared ADHF patients without renal impairment to CRS1 patients. The markers of oxidative stress, which included myeloperoxidase, nitric oxide, copper/zinc superoxide dismutase, and endogenous peroxidase, were all significantly higher in CRS1 patients [13]. While provocative, the tissues responsible for the generation of these molecules and the subsequent effects have not yet been fully elucidated.

The proposed pathophysiology is seen in the Figure.

Prognostication

Severity of Acute Kidney Injury

Initial publications did not document a strong link between kidney injury and poor outcomes in ADHF. Firstly, Ather et al performed a single-centered study that investigated how change in renal function defined by change in creatinine, estimated GFR, and BUN affected outcomes one year post admission for ADHF. Kidney injury defined by a change in creatinine or in estimated GFR was not associated with increased risk of mortality, but a change in BUN was associated with increased mortality in a univariate analysis [15]. Testani et al retrospectively analyzed patients from the ESCAPE trial and found worsening renal function defined by a ≥ 20% reduction in estimated GFR was not significantly associated with 180-day mortality, but there was a trend towards higher mortality (hazard ration 1.4; P = 0.11) [16]. Importantly, neither of 2 these studies assessed how severity of AKI impacted outcomes, which may have contributed to the weak relationships observed.

However, when AKI severity in CRS1 was quantified, poor outcomes were more likely as AKI severity increased. Firstly, Roy et al determined how AKI impacted adverse events (mortality, rehospitalization, or need for dialysis) rates in 637 patients with ADHF. Severity of AKI was quantified using RIFLE, AKIN, and KDIGO guidelines (Table 1), and the authors found that as the severity of renal injury increased, the likelihood of an adverse event was higher. In fact, the most severe AKI grade using all 3 AKI grading systems resulted in an odds ratio ranging from 45.3 to 101.6 for an adverse event at 30 days when compared to no kidney injury [7]. Hata et al documented that AKI (defined using RIFLE criteria) in ADHF resulted in a longer ICU stay, total hospital length of stay, and higher in-hospital mortality rates, and patients with a failure-grade AKI had in-hospital mortality rate of 49.1% [17]. Finally, Li et al evaluated AKI in 1005 patients with ADHF and showed that AKI defined by RIFLE, AKIN, or KDIGO methods increased risk of in-hospital mortality, and that a KDIGO grade 3 AKI was associated with a 35.5% in-hospital mortality rate [8]. These data indicate CRS1 is associated with poor outcomes, and there is a heightened risk of adverse events as AKI severity increases.

Diuretic Responsiveness

Using change in serum creatinine as a marker of renal impairment may not be the best choice for predicting outcomes in CRS1 because the lab values are not a real-time measure of kidney function and serum creatinine can be affected by both body mass and pharmaceutical agents. Therefore, the prognosticating ability of urine production relative to diuretic dose as a surrogate measure of renal function in ADHF was investigated by several groups (Table 2). Testani et al examined urine output per 40 mg of furosemide and tracked outcomes in 2 cohorts: patients admitted with ADHF at the University of Pennsylvania (657 patients) and patients from the ESCAPE trial (390 patients). Patients were split into high responders or low responders based on the median value. In both of the patient cohorts, low diuretic efficiency was associated with increased mortality using a multivariate model (hazard ratio of 1.36 in the Penn patients and 2.86 in the ESCAPE patients). The combination of low diuretic efficiency and high diuretic dose (> 280 mg in the Penn cohort and > 240 mg in the ESCAPE cohort) resulted in the worst prognosis, with mortality rates of approximately 70% at 6 years in the Penn cohort and approximately 35% at 180 days in the ESCAPE cohort [18].

Voors et al performed a retrospective analysis of diuretic responsiveness in 1161 patients from the Relaxin in Acute Heart Failure (RELAX-AHF) trial. Diuretic responsiveness was defined as weight change (kg) per diuretic dose (IV furosemide and PO furosemide) over 5 days and then patients were separated into tertiles. The lowest tertile group had an approximate 20% incidence of 60-day combined end-point of death, heart failure or renal failure readmission compared to less than 10% incidence in the middle and upper tertiles. Interestingly, when the effects of worsening renal function (WRF), defined as creatinine change of ≥ 0.3 mg/dL, were examined in patients stratified by diuretic response, WRF did not offer additional prognostic information [19].

Finally, Valenete et al analyzed diuretic response in 1745 patients from the PROTECT trial (Placebo-Controlled Randomized Study of the Selective A1-Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function). Diuretic response was calculated using the weight change per 40 mg of furosemide, and as diuretic response declined there was increasing risk of 60-day rehospitalization and 180-day mortality rates. In fact, the lowest quintile responders had a 25% mortality rate at 180 days [20].

Emerging Biomarkers

Urine Neutrophil Gelatinase-Associated Lipocalin

Because previous studies showed urinary levels of NGAL was an earlier and more reliable marker of renal dysfunction than creatinine in AKI [21], it was studied as a possible biomarker for the development of CRS1 in ADHF. A single-centered study quantified levels of urine NGAL in 100 patients admitted with heart failure and then tracked the rates of acute kidney injury. Urine NGAL was elevated in patients that developed AKI and a cut-off value 12 ng/mL had a sensitivity of 79% and specificity of 67% for predicting CRS1 [22]. While promising, further studies are needed to better define the role of NGAL in CRS1.

Cystatin C

Cystatin C is a ubiquitously expressed cysteine protease that has a constant production rate and is freely filtered by the glomerulus without being secreted into the tubules, and has effectively prognosticated outcomes in ADHF [23]. Lassus et al showed an adjusted hazard ratio of 3.2 (2.0–5.3) for 12-month mortality when cystatin C levels were elevated. Moreover, patients with the highest tertitle of NT-proBNP and cystatin C had a 48.7% 1-year mortality. Interestingly, patients with an elevated cystatin C but normal creatinine had a 40.6% 1-year mortality compared to 12.6% for those with normal cystatin C and creatinine [24]. Furthermore, Arimoto et al showed elevated cystatin C predicted death or rehospitalization in a small cohort of ADHF patients in Japan [25]. Also, Naruse et al showed cystatin C was a better predictor of cardiac death than estimated GFR by the Modification of Diet in Renal Disease Study (MDRD) equation [26]. Finally, Manzano-Fernandez et al showed the highest tertile of cystatin C was a significant independent risk factor for 2-year death or rehospitalization while creatinine and MDRD estimates of GFR were not [27]. In agreement with Lassus et al, elevations in either 2 or 3 of cystatin C, troponin, and NT-proBNP predicted death or rehospitalization when compared to those with normal levels of these 3 markers [27]. In conclusion, cystatin C either alone or in combination with other biomarkers identifies high-risk patients.

Kidney Injury Molecule 1

Kidney injury molecule 1 (KIM-1) is a type-1 cell membrane glycoprotein expressed in regenerating proximal tubular cells but not under normal conditions [28]. Although associated with increased risk of hospitalization and mortality in chronic heart failure [29,30], elevated levels of urinary KIM-1 did not predict mortality in ADHF [31]. Further studies are needed to elucidate the utility of KIM-1 in CRS1.

Treatment Approaches

Diuretics

Loop diuretics are the main treatment for decongestion of patients with CRS1. To date, no clinical trial has compared the different loop diuretics (furosemide, bumetanide, torsemide, or ethacrynic acid) to each other, so there is no clear choice of which loop diuretic is the best. However, dosing scheme was investigated in the Dose Optimization Strategies Evaluation (DOSE) trial. In this trial, 308 patients were randomized in a 1:1:1:1 design in which patients were placed in groups with low-dose (equivalent to oral dose) or high-dose (2.5 times oral dose) intermittent parental therapy or alternatively low-dose or high-dose continuous drip therapy. There were no differences in dyspnea, fluid changes, change in creatinine, hospital length stay, or rehospitalization and death rates when the intermittent and drip approaches were compared. However, the high-dose arm had decreased dyspnea, increased volume removal, but there were more occurrences of AKIs when compared to the low-dose arm [32].

In clinical practice, if loop diuretic treatment does not result in the desired urine output, a second-site diuretic may be added to potentiate diuresis. Unfortunately, there is little data on this common clinical practice and thus the optimal choice of second site agent (chlorthiazide or metolazone) is unknown. Frequently, the deciding factor is based upon cost or concern that oral absorption of metolazone will be ineffective. However, Moranville et al recently performed a retrospective assessment comparing chlorthiazide (22 patients) to metolazone (33 patients) in ADHF patients with renal dysfunction defined by a creatinine clearance of 15–50 mL/min. There was a nonsignificant trend towards increased urine output in the metolazone group, no differences in the rates of adverse events, and the chlorthiazide group actually had a longer hospital stay [33]. While potentially promising results, the retrospective nature of the study made it difficult to determine if the differences were due to treatment approach or dissimilarities of patient illness. Nonetheless, physicians must remain vigilant when implementing the second-site diuretic approach because it can lead to marked diuretic response leading to metabolic derangements including hypokalemia, hyponatremia, hypomagnesaemia, and metabolic alkalosis.

Inotropes

The use of inotropic agents such as dobutamine or milrinone can be used to augment cardiac function when there is a known low-output state for better renal perfusion in CRS1. Unfortunately, there is little objective data available about the utility of this widely implemented approach. The Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of a Chronic Heart Failure (OPTIME-HF) trial did not show improved renal function with milrinone treatment [34]. The use of levosimendan, a cardiac calcium sensitizer that increases contractility not currently approved in the United States, was compared to dobutamine in the Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support (SURVIVE) trial, and there were no differences in rates of renal failure when the 2 groups were compared [35]. Nonetheless, if cardiac output is severely compromised, inotropes can be used for CRS1 treatment, but they should be used cautiously due the increased risks of lethal arrhythmias.

Dopamine

Use of low-dose dopamine to stimulate D1 and D2 receptors as a way to increase renal blood flow and promote increased glomerular filtration and urine production was extensively studied in ADHF. A small trial showed use of low dose dopamine had renal protective effects in a total of 20 patients [36]. However, when larger trials were conducted, such beneficial results were not consistently observed. The Dopamine in Acute Decompensated Heart Failure (DAD-HF I) trial compared low-dose furosemide plus low-dose dopamine (5 µg/kg/min) to high-dose furosemide alone in 60 patients. There were no differences in total diuresis, hospital stay, and 60-day mortality or rehospitalization rates, but there was a reduction in the renal dysfunction at the 24-hour time point in the dopamine-treated arm (6.7% versus 30%) [37]. The Dopamine in Acute Decompensated Heart Failure II trial randomized 161 ADHF patients to high-dose furosemide, low-dose furosemide and lose dose dopamine (5 µg/kg/min), or low-dose furosemide and assessed dyspnea, worsening renal function, length of stay, 60-day and one-year all-cause mortality and hospitalization for heart failure. Dopamine treatment did not improve any of the outcomes measured [38]. Finally, the most recent trial to examine the effects of dopamine was the Renal Optimization Strategies Evaluation (ROSE) trial. In this trial, there were 360 patients with ADHF randomized to nesiritide or dopamine versus placebo in a 2:1 design. When comparing dopamine (111 patients) treatment to placebo (115 patients), there were no differences in urine output, renal function as determined by cystatin C levels, or symptomatic improvements. However, there was more tachycardia in the dopamine group [39]. Currently, there is not strong evidence supporting routine use of dopamine in CRS1.

Nesiritide

Use of nesiritide, recombinant brain natriuretic peptide, was also investigated as a way to enhance urine production through the natriuretic effects of the peptide. The first attempt to explore this hypothesis was the B-Type Natriuretic Peptide in Cardiorenal Decompensation Syndrome (BNP-CARDS) trial. BNP-CARDS showed a 48-hour infusion of nesiritide (39 patients) or placebo (36 patients) in patients with ADHF and renal dysfunction (estimated GFR between 15–60 mL/min) did not reduce the incidence of worsening renal function as defined by a rise in serum creatinine by 20% [40]. A similar approach was implemented in the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial which examined over 7000 patients with ADHF. 3496 patients were treated with nesiritide and 3511 patients were treated with placebo for 24 hours and up to 7 days. Nesiritide treatment did not alter dyspnea at 6 and 24 hours, improve renal function as determined by creatinine change, or alter the combined end-point of rehospitalization or death 30 at days [41]. The ROSE trial examined the effects of nesiritide (117 patients) versus placebo (115 patients) for urine production, change in renal function as defined by change in cystatin C, and decongestion (urinary sodium excretion, weight change, and change in NT-proBNP) at 72 hours. Nesiritide did not alter any of the outcomes investigated [39]. Finally, a single-centered study conducted at the Mayo Clinic examined the effects of nesiritide (37 patients) or placebo (35 patients) with ADHF and pre-existing renal dysfunction (estimated GFR between 20 and 60 mL/min). These investigators found nesiritide treatment resulted in less renal dysfunction as measured by creatinine and BUN, but no changes in diuretic responsiveness, duration of hospitalization, or rehospitalization rates. Nesiritide did reduce serum endothelin levels, but had no effect on ANP, NT-pro BNP, renin, angiotensin II, or aldosterone [42]. In summary, nesiritide does not appear to have significant renal protective effects in ADHF.

Adenosine A1 Receptor Antagonists

The use of adenosine receptor antagonists to prevent adenosine-mediated vasoconstriction of renal vasculature in ADHF has also been examined. The first study conducted was a small double-blind randomized-controlled trial that investigated the effects of rolofylline, an adenosine A-1 antagonist, in patients with ADHF and an estimated creatinine clearance of 20-80 mL/min. The study had 27 patients in the placebo arm, 29 patients that received 2.5 mg of rolofylline, 31 patients received 15 mg of rolofylline, 30 patients received 30 mg of rolofylline, and 29 patients received 60 mg of rolofylline, all of which was daily for up to 3 days. Rolofylline treatment increased urine output on day 1 and improved renal function on day 2 [43]. These positive results led to the Placebo-Controlled Randomized Study of Selective Adenosine A1 Receptor Antagonist Rolofylline for Patients with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function (PROTECT) Trial. PROTECT assessed the effects of rolofylline (1356) or placebo (677) in patients with ADHF and an estimated creatinine clearance between 20 and 80 mL/min. There were no significant differences in renal function out to 14 days, but rolofylline led to more weight loss than placebo [44,45]. In a subgroup analysis of patients with severe baseline renal dysfunction (creatinine clearance of less than 30 mL/min), rolofylline reduced the combined 60-day end-point of hospitalization due to cardiovascular or renal cause and death [45]. Finally, the Effects of KW-3902 Injectable Emulsion on Heart Failure Signs and Symptoms, Diuresis, Renal Function, and Clinical Outcomes in Subjects Hospitalized with Worsening Renal Function and Heart Failure Requiring Intravenous Therapy (REACH-UP) trial probed the effects of rolofylline (36 patients) or placebo (40 patients) in patients with ADHF and renal impairment (creatinine clearance of 20-60 mL/min). Rolofylline treatment did not alter renal function, but there was a nonsignificant trend towards reduction in 60-day combined end-point of hospitalization due to renal or cardiovascular causes or death [46]. In summary, the use of rolofylline has not been conclusively associated with improved outcomes in CRS1.

Vasopressin Antagonists

The use of vasopressin antagonists to induce aquaphoresis and combat hyponatremia was studied in ADHF. Vasopressin antagonists were first investigated in the Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist (ACTIV) trial. ACTIV involved 3 doses of tolvaptan (78 patients received 30 mg, 84 patients received 60 mg, and 77 patients received 90 mg) versus placebo (80 patients), and tolvaptan increased urine production and decreased body weight compared to placebo without compromising renal function. A post-hoc analysis of patients with renal dysfunction (BUN > 29 mg/dL) and severe volume overload revealed a survival benefit at 60 days [47]. The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVERST) trial compared placebo (2061 patients) versus 30 mg/day of tolvaptan (2072 patients) within 48 hours after admission in an identical 2-trial design. Tolvaptan increased weight loss and reduced dyspnea acutely but did not alter all-cause mortality or cardiovascular or heart failure hospitalization rates out to 24 months post index hospitalization [48,49]. These data suggest vasopressin antagonists may potentiate diuresis acutely but likely do not improve long-term outcomes.

Corticosteroids

The use of corticosteroids in ADHF has been controversial as there were initial concerns that corticosteroids would increase fluid retention. However, corticosteroids augmented diuretic response and improved renal function in 13 ADHF patients who had inadequate response to sequential nephron blockage [50]. Furthermore, Zhang et al showed that prednisone treatment in 35 patients admitted with ADHF increased urinary volume, reduced dyspnea, reduced uric acid, and improved renal function [51]. These promising results led to the Cardiac Outcome Prevention Effectiveness of Glucocorticoids in Acute Decompensated Heart Failure (COPE-ADHF) trial. In this single-centered study, 102 patients with ADHF were randomized to either placebo [51] or corticosteroids [51] and the outcomes recorded included urinary volume, change in creatinine, and cardiovascular death at 30 days. Use of corticosteroids improved renal function, increased urine output, and reduced mortality (3/51 in corticosteroid group versus 10/51 in the placebo group) [52]. The mechanisms underlying the improvements with corticosteroids were not determined, but were hypothesized to be facilitation of natriuretic peptides or dilation of renal vasculature through activation of nitric oxide pathway or dopaminergic system.

Serelaxin

Serelaxin is a recombinantly expressed human relaxin-2, a peptide hormone present during pregnancy which facilitates physiological cardiovascular and renal adaptations [53–55], which showed potential benefits in CRS1. Analysis of the RELAX-AHF trial revealed serelaxin reduced incidence of worsening renal function at day 2 of treatment as defined by changes in serum creatinine, cystatin C, and BUN. Importantly, worsening renal function defined by cystatin C changes was associated with increased 180-day mortality in this analysis [56]. The mechanisms by which serelaxin prevented renal dysfunction are currently unknown as serelaxin treatment did not improve diuretic efficiency [19].

Ultrafiltration

Another treatment choice in CRS1 is mechanical removal of salt and water via ultrafiltration. Ultrafiltration showed early promise in Ultrafiltration Versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Heart Failure trial (UNLOAD) trial. In this study, 200 patients with ADHF were randomized to either ultrafiltration or medical management with loop diuretics. Use of ultrafiltration increased volume removal without any differences in renal function and reduced rehospitalization rates at 90 days [57].

However, when ultrafiltration was employed specifically in CRS1 patients in the Cardiorenal Rescue Study in Acute Decompensated Heart Failure trial (CARESS-HF), UF was not superior to medical treatment. There were 188 patients studied in CARESS-HF, and in the ultrafiltration arm there was increased risk of renal dysfunction, no differences in volume removal, and no change in rehospitalization rates at 90 days [58]. When trying to reconcile UNLOAD and CARESS-HF, the medical treatment arm in CARESS-HF was much more standardized and aggressive and UNLOAD was earlier implementation of ultrafiltration, which may have explained the differences. Interestingly, ultrafiltration was hypothesized to be advantageous over diuretic therapy through reduced activation of the renin-angiotensin-aldosterone system, but analysis of the patients from CARESS-HF showed higher levels of plasma renin activity and no difference in aldosterone levels in ultrafiltration patients [59].

Two meta-analyses have examined the use of ultrafiltration versus medical management in ADHF and both showed ultrafiltration was more effective in volume removal than medical therapy but did not improve rehospitalization or mortality rates [60,61]. This fact combined with the risks of vascular access placement and bleeding from anticoagulation limits to routine use of ultrafiltration in CRS1.

Continuous Renal Replacement Therapy

Once renal function deteriorates to the point that renal replacement therapy is needed for both volume removal and solute clearance in CRS1, continuous renal replacement therapy (CRRT) may be implemented. Unfortunately, there are few available data for this group of advanced CRS1 patients to guide physicians. There was a single-centered study conducted in Egypt that randomized 40 ADHF patients to either IV furosemide or CRRT. The patients treated with CRRT had greater weight loss and decreased length of stay in the ICU, but there were no differences in dialysis dependence rates or 30-day mortality [62]. Two single-centered studies reported outcomes associated with advanced CRS1 requiring CRRT. In a study conducted at the Cleveland Clinic, 63 patients with CRS1 were treated with ultrafiltration, of which 37 were converted to CRRT due to worsening renal function. Of the 37 patients treated with CRRT, 16 died in the hospital and 4 were discharged with hospice care [63]. In another retrospective study performed at the University of Alabama-Birmingham, use of rescue CRRT in advanced CRS1 was examined in 37 patients. 23 patients died during hospitalization and 2 were discharged to hospice care [64]. Combination of the Cleveland Clinic and University of Alabama-Birmingham studies revealed patients requiring CRRT in the setting of advanced CRS1 had an in-hospital mortality or palliative discharge rate of 60.8% (45/74). Clearly, this population needs further investigation to prevent such poor outcomes.

A summary of treatment approaches for CRS1 is presented in Table 3.

Future Treatment Options

Ongoing and Unreported Clinical Trials

Unfortunately, none of the current treatments for CRS1 have definitive improvements in outcomes, but there are several ongoing clinical trials which will hopefully identify novel treatment strategies. First of all, the Acetazolamide and Spironolactone to Increase Natriuresis in Congestive Heart Failure (Diuresis-CHF) trial is being conducted in Belgium. This study will examine the effects of acetazolamide with low dose diuretic versus high dose diuretics in one aim and the effects of upfront spironolactone in another. The outcomes analyzed will include total natriuresis, potassium homeostasis, NT-proBNP changes, change in renal function, peak serum levels of renin and aldosterone, weight change, urine volume, and change in edema (NCT01973335). The Protocolized Diuretic Strategy in Cardiorenal Failure (ProDius) trial is being performed at the University of Pittsburgh, and will determine the effects of a protocolized diuretic approach to target 3-5 liters of urine production a day versus standard therapy and will track the change in body weight, length of hospitalization, reshospitalization rates, mortality rates, venous compliance of internal jugular vein, clinical decongestion, change in renal function, and urine output (NCT01921829). The Levosimendan versus Dobutamine for Renal Function in Heart Failure (ELDOR) study is ongoing in Sweden and will probe the acute effects of levosimendan and dobutamine on renal perfusion. The endpoints will include changes in renal blood flow, GFR, renal vascular resistance, central hemodynamics, renal oxygen extraction and consumptions, and filtration fraction (NCT02133105). Finally, the Safety and Efficacy of Low Dose Hypertonic Saline and High Dose Furosemide for Congestive Heart Failure (REaCH) trial probed the effects of combination of hypertonic saline and furosemide versus furosemide in patients with ADHF and renal impairment defined by a GFR<60 mL/min. The outcomes were change in renal function, diuretic response, length of hospital stay, readmission rates, weight loss, BNP levels, and included a cost analysis. The study was completed but results are not currently available (NCT01028170)

Should Inflammation Be Targeted in CRS1?

Although proposed to play a role in the pathophysiology of CRS1, inflammation has not been explicitly targeted as a treatment for CRS1. One possible way to combat inflammation could be inhibition of the IL-6 pathway, which is support by preclinical work as previous studies showed IL-6 knockout mice were resistant to HgCl₂-induced renal injury and death [65] and IL-6 has negative inotropic effects in both isolated cardiomyocytes [66] and intact animals [67]. Thus, IL-6 antagonism may improve both cardiac and renal function, an ideal scenario for CRS1 patients. The availability of tocilizumab, an FDA-approved humanized antibody to the IL-6 receptor, may allow for investigation of this hypothesis in the future. Although not examined in the COPE-ADHF trial, an alternative explanation for the improvements associated with corticosteroids treatment were the anti-inflammatory effects. If this were true, corticosteroids would represent a relatively cheap treatment option for CRS1 patients, but more studies need to be conducted before this approach is widely implemented. Finally, use of cytokine profiling may be used to enrich a population of CRS1 patients that could be investigated in future clinical trials using anti-inflammatory medications.

Unanswered Questions Moving Forward

Severity of AKI and Treatment Effects

An important unknown that warrants further investigation is if the severity of AKI should dictate treatment choice in CRS1. As discussed above, increasing severity of AKI resulted in elevated risk of adverse events, but it remains unknown whether different treatments offer benefits for more or less severe renal impairment. Perhaps, future studies aimed at defining outcomes from different treatment strategies stratified by severity of renal dysfunction may reveal which patients benefit from the various treatment options for CRS1.

How Do We Best Define Renal Dysfunction in CRS1?

Currently, there is no accepted definition of renal dysfunction in CRS1. As discussed above, using the AKIN, KDIGO, or RIFLE scoring systems or diuretic responsiveness effectively differentiated outcomes in patients with CRS1. However, an agreed-upon definition would likely benefit the field going forward so this population could be systematically investigated in future studies.

Conclusion

In summary, CRS1 is a common clinical entity associated with poor patient outcomes. A complex pathophysiology marked by reduced cardiac output, increased central venous pressure, inflammation, and oxidative stress underlies the disease process. Unfortunately, no current treatment approach shows consistent improvements in outcomes, highlighting the urgent need for further research to reduce the burden that CRS1 imposes.

 

Corresponding author: Kurt W. Prins, MD, PhD, MMC 580 Mayo, 420 Delaware St SE, Minneapolis, MN 55455, [email protected].

Funding/support: Dr. Prins is funded by NIH F32 grant HL129554 and Dr. Thenappen is funded by AHA Scientist Development Grant 15SDG25560048.

From the Cardiovascular Division, Department of Internal Medicine, University of Minnesota, Minneapolis, MN.

 

Abstract

• Objective: To present a review of cardiorenal syndrome type 1 (CRS1).
• Methods: Review of the literature.
• Results: Acute kidney injury occurs in approximately one-third of patients with acute decompensated heart failure (ADHF) and the resultant condition was named CRS1. A growing body of literature shows CRS1 patients are at high risk for poor outcomes, and thus there is an urgent need to understand the pathophysiology and subsequently develop effective treatments. In this review we discuss prevalence, proposed pathophysiology including hemodynamic and nonhemodynamic factors, prognosticating variables, data for different treatment strategies, and ongoing clinical trials and highlight questions and problems physicians will face moving forward with this common and challenging condition.
• Conclusion: Further research is needed to understand the pathophysiology of this complex clinical entity and to develop effective treatments.

 

Acute decompensated heart failure (ADHF) is an epidemic facing physicians throughout the world. In the United States alone, ADHF accounts for over 1 million hospitalizations annually, with costs in 2012 reaching $30.7 billion [1]. Despite the advances in chronic heart failure management, ADHF continues to be associated with poor outcomes as exemplified by 30-day readmission rates of over 20% and in-hospital mortality rates of 5% to 6%, both of which have not significantly improved over the past 20 years [2,3]. One of the strongest predictors of adverse outcomes in ADHF is renal dysfunction. An analysis from the Acute Decompensated Heart Failure National Registry (ADHERE) revealed the combination of renal dysfunction (creatinine > 2.75 mg/dL and blood urea nitrogen (BUN) > 43 mg/dL) and hypotension (systolic blood pressure (SBP) < 115 mm Hg) upon admission was associated with an in-hospital mortality of > 20% [4]. The Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) registry documented a 16.3% in-hospital mortality when patients had a SBP < 100 mm Hg and creatinine > 2.0 mg/dL at admission [5].

The presence of acute kidney injury in the setting of ADHF is a very common occurrence and was termed cardiorenal syndrome type 1 (CRS1) [6]. The prevalence of CRS1 in single-centered studies ranged from 32% to 40% of all ADHF admissions [7,8]. If this estimate holds true throughout the United States, there would be 320,000 to 400,000 hospitalizations for CRS1 annually, highlighting the magnitude of this problem. Moreover, with the number of patients with heart failure expected to continue to rise, CRS1 will only become more prevalent in the future. In this review we discuss the prevalence, proposed pathophysiology including hemodynamic and nonhemodynamic factors, prognosticating variables, data for different treatment strategies, ongoing clinical trials, and highlight questions and problems physicians will face moving forward in this common and challenging condition.

Pathogenesis of CRS1

Hemodynamic Effects

The early hypothesis for renal dysfunction in ADHF centered on hemodynamics, as reduced cardiac output was believed to decrease renal perfusion. However, analysis of invasive hemodynamics from patients with ADHF suggested that central venous pressure (CVP) was actually a better predictor of the development of CRS1 than cardiac output. In a single-center study conducted at the Cleveland Clinic, hemodynamics from 145 patients with ADHF were evaluated and surprisingly baseline cardiac index was greater in the patients with CRS1 than patients without renal dysfunction (2.0 ± 0.8 L/min/m² vs 1.8 ± 0.4 L/min/m²; P = 0.008). However, baseline CVP was higher in the CRS1 group (18 ± 7 mm Hg vs 12 ± 6 mm Hg; P = 0.001), and there was a heightened risk of developing CRS1 as CVP increased. In fact, 75% of the patients with a CVP of > 24 mm Hg developed renal impairment [9]. In a retrospective study of the Evaluation Study of Congestive Heart Failure and Pulmonary Arterial Catheter Effectiveness (ESCAPE) trial, the only hemodynamic parameter that correlated with baseline creatinine was CVP. However, no invasive measures predicted worsening renal function during hospitalization [10]. Finally, an experiment that used isolated canine kidneys showed increased venous pressure acutely reduced urine production. Interestingly, this relationship was dependent on arterial pressure; as arterial flow decreased smaller increases in CVP were needed to reduce urine output [11]. Together, these data suggest increased CVP plays an important role in CRS1, but imply hemodynamics alone may not fully explain the pathophysiology of CRS1.

Inflammation

As information about how hemodynamics incompletely predict renal dysfunction in ADHF became available, alternative hypotheses were investigated to gain a deeper understanding of the pathophysiology underlying CRS1. A pathological role of inflammation in CRS1 has gained attention due to recent publications. First of all, serum levels of the pro-inflammatory cytokines TNF-a and IL-6 were elevated in patients with CRS1 when compared to health controls [12]. Interestingly, Virzi et al showed that the median value of IL-6 was 5 times higher in CRS1 patients when compared to ADHF patients without renal dysfunction [13]. The negative consequences of elevated serum cytokines were demonstrated when incubation of a human cell line of monocytes with serum from CRS1 patients induced apoptosis in 81% of cells compared to just 11% of cells with control serum [12]. It is possible that cytokine-induced apoptosis could occur in other cell types in different organs in patients with CRS1, which may contribute to both cardiac and renal dysfunction. Finally, analysis from a rat model of CRS1 revealed macrophage infiltration into the kidneys and increased numbers of activated monocytes in the peripheral blood. Interestingly, monocyte/macrophage depletion using liposome clodronate prevented chronic renal dysfunction in the rat model [14]. In summary, these data suggest inflammation contributes to CRS1 pathophysiology, but more experimental data is needed to determine if there is a causal relationship.

Oxidative Stress

Very recently, oxidative stress was proposed to play a role in CRS1. Virzi et al analyzed serum levels of markers of oxidative stress and compared ADHF patients without renal impairment to CRS1 patients. The markers of oxidative stress, which included myeloperoxidase, nitric oxide, copper/zinc superoxide dismutase, and endogenous peroxidase, were all significantly higher in CRS1 patients [13]. While provocative, the tissues responsible for the generation of these molecules and the subsequent effects have not yet been fully elucidated.

The proposed pathophysiology is seen in the Figure.

Prognostication

Severity of Acute Kidney Injury

Initial publications did not document a strong link between kidney injury and poor outcomes in ADHF. Firstly, Ather et al performed a single-centered study that investigated how change in renal function defined by change in creatinine, estimated GFR, and BUN affected outcomes one year post admission for ADHF. Kidney injury defined by a change in creatinine or in estimated GFR was not associated with increased risk of mortality, but a change in BUN was associated with increased mortality in a univariate analysis [15]. Testani et al retrospectively analyzed patients from the ESCAPE trial and found worsening renal function defined by a ≥ 20% reduction in estimated GFR was not significantly associated with 180-day mortality, but there was a trend towards higher mortality (hazard ration 1.4; P = 0.11) [16]. Importantly, neither of 2 these studies assessed how severity of AKI impacted outcomes, which may have contributed to the weak relationships observed.

However, when AKI severity in CRS1 was quantified, poor outcomes were more likely as AKI severity increased. Firstly, Roy et al determined how AKI impacted adverse events (mortality, rehospitalization, or need for dialysis) rates in 637 patients with ADHF. Severity of AKI was quantified using RIFLE, AKIN, and KDIGO guidelines (Table 1), and the authors found that as the severity of renal injury increased, the likelihood of an adverse event was higher. In fact, the most severe AKI grade using all 3 AKI grading systems resulted in an odds ratio ranging from 45.3 to 101.6 for an adverse event at 30 days when compared to no kidney injury [7]. Hata et al documented that AKI (defined using RIFLE criteria) in ADHF resulted in a longer ICU stay, total hospital length of stay, and higher in-hospital mortality rates, and patients with a failure-grade AKI had in-hospital mortality rate of 49.1% [17]. Finally, Li et al evaluated AKI in 1005 patients with ADHF and showed that AKI defined by RIFLE, AKIN, or KDIGO methods increased risk of in-hospital mortality, and that a KDIGO grade 3 AKI was associated with a 35.5% in-hospital mortality rate [8]. These data indicate CRS1 is associated with poor outcomes, and there is a heightened risk of adverse events as AKI severity increases.

Diuretic Responsiveness

Using change in serum creatinine as a marker of renal impairment may not be the best choice for predicting outcomes in CRS1 because the lab values are not a real-time measure of kidney function and serum creatinine can be affected by both body mass and pharmaceutical agents. Therefore, the prognosticating ability of urine production relative to diuretic dose as a surrogate measure of renal function in ADHF was investigated by several groups (Table 2). Testani et al examined urine output per 40 mg of furosemide and tracked outcomes in 2 cohorts: patients admitted with ADHF at the University of Pennsylvania (657 patients) and patients from the ESCAPE trial (390 patients). Patients were split into high responders or low responders based on the median value. In both of the patient cohorts, low diuretic efficiency was associated with increased mortality using a multivariate model (hazard ratio of 1.36 in the Penn patients and 2.86 in the ESCAPE patients). The combination of low diuretic efficiency and high diuretic dose (> 280 mg in the Penn cohort and > 240 mg in the ESCAPE cohort) resulted in the worst prognosis, with mortality rates of approximately 70% at 6 years in the Penn cohort and approximately 35% at 180 days in the ESCAPE cohort [18].

Voors et al performed a retrospective analysis of diuretic responsiveness in 1161 patients from the Relaxin in Acute Heart Failure (RELAX-AHF) trial. Diuretic responsiveness was defined as weight change (kg) per diuretic dose (IV furosemide and PO furosemide) over 5 days and then patients were separated into tertiles. The lowest tertile group had an approximate 20% incidence of 60-day combined end-point of death, heart failure or renal failure readmission compared to less than 10% incidence in the middle and upper tertiles. Interestingly, when the effects of worsening renal function (WRF), defined as creatinine change of ≥ 0.3 mg/dL, were examined in patients stratified by diuretic response, WRF did not offer additional prognostic information [19].

Finally, Valenete et al analyzed diuretic response in 1745 patients from the PROTECT trial (Placebo-Controlled Randomized Study of the Selective A1-Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function). Diuretic response was calculated using the weight change per 40 mg of furosemide, and as diuretic response declined there was increasing risk of 60-day rehospitalization and 180-day mortality rates. In fact, the lowest quintile responders had a 25% mortality rate at 180 days [20].

Emerging Biomarkers

Urine Neutrophil Gelatinase-Associated Lipocalin

Because previous studies showed urinary levels of NGAL was an earlier and more reliable marker of renal dysfunction than creatinine in AKI [21], it was studied as a possible biomarker for the development of CRS1 in ADHF. A single-centered study quantified levels of urine NGAL in 100 patients admitted with heart failure and then tracked the rates of acute kidney injury. Urine NGAL was elevated in patients that developed AKI and a cut-off value 12 ng/mL had a sensitivity of 79% and specificity of 67% for predicting CRS1 [22]. While promising, further studies are needed to better define the role of NGAL in CRS1.

Cystatin C

Cystatin C is a ubiquitously expressed cysteine protease that has a constant production rate and is freely filtered by the glomerulus without being secreted into the tubules, and has effectively prognosticated outcomes in ADHF [23]. Lassus et al showed an adjusted hazard ratio of 3.2 (2.0–5.3) for 12-month mortality when cystatin C levels were elevated. Moreover, patients with the highest tertitle of NT-proBNP and cystatin C had a 48.7% 1-year mortality. Interestingly, patients with an elevated cystatin C but normal creatinine had a 40.6% 1-year mortality compared to 12.6% for those with normal cystatin C and creatinine [24]. Furthermore, Arimoto et al showed elevated cystatin C predicted death or rehospitalization in a small cohort of ADHF patients in Japan [25]. Also, Naruse et al showed cystatin C was a better predictor of cardiac death than estimated GFR by the Modification of Diet in Renal Disease Study (MDRD) equation [26]. Finally, Manzano-Fernandez et al showed the highest tertile of cystatin C was a significant independent risk factor for 2-year death or rehospitalization while creatinine and MDRD estimates of GFR were not [27]. In agreement with Lassus et al, elevations in either 2 or 3 of cystatin C, troponin, and NT-proBNP predicted death or rehospitalization when compared to those with normal levels of these 3 markers [27]. In conclusion, cystatin C either alone or in combination with other biomarkers identifies high-risk patients.

Kidney Injury Molecule 1

Kidney injury molecule 1 (KIM-1) is a type-1 cell membrane glycoprotein expressed in regenerating proximal tubular cells but not under normal conditions [28]. Although associated with increased risk of hospitalization and mortality in chronic heart failure [29,30], elevated levels of urinary KIM-1 did not predict mortality in ADHF [31]. Further studies are needed to elucidate the utility of KIM-1 in CRS1.

Treatment Approaches

Diuretics

Loop diuretics are the main treatment for decongestion of patients with CRS1. To date, no clinical trial has compared the different loop diuretics (furosemide, bumetanide, torsemide, or ethacrynic acid) to each other, so there is no clear choice of which loop diuretic is the best. However, dosing scheme was investigated in the Dose Optimization Strategies Evaluation (DOSE) trial. In this trial, 308 patients were randomized in a 1:1:1:1 design in which patients were placed in groups with low-dose (equivalent to oral dose) or high-dose (2.5 times oral dose) intermittent parental therapy or alternatively low-dose or high-dose continuous drip therapy. There were no differences in dyspnea, fluid changes, change in creatinine, hospital length stay, or rehospitalization and death rates when the intermittent and drip approaches were compared. However, the high-dose arm had decreased dyspnea, increased volume removal, but there were more occurrences of AKIs when compared to the low-dose arm [32].

In clinical practice, if loop diuretic treatment does not result in the desired urine output, a second-site diuretic may be added to potentiate diuresis. Unfortunately, there is little data on this common clinical practice and thus the optimal choice of second site agent (chlorthiazide or metolazone) is unknown. Frequently, the deciding factor is based upon cost or concern that oral absorption of metolazone will be ineffective. However, Moranville et al recently performed a retrospective assessment comparing chlorthiazide (22 patients) to metolazone (33 patients) in ADHF patients with renal dysfunction defined by a creatinine clearance of 15–50 mL/min. There was a nonsignificant trend towards increased urine output in the metolazone group, no differences in the rates of adverse events, and the chlorthiazide group actually had a longer hospital stay [33]. While potentially promising results, the retrospective nature of the study made it difficult to determine if the differences were due to treatment approach or dissimilarities of patient illness. Nonetheless, physicians must remain vigilant when implementing the second-site diuretic approach because it can lead to marked diuretic response leading to metabolic derangements including hypokalemia, hyponatremia, hypomagnesaemia, and metabolic alkalosis.

Inotropes

The use of inotropic agents such as dobutamine or milrinone can be used to augment cardiac function when there is a known low-output state for better renal perfusion in CRS1. Unfortunately, there is little objective data available about the utility of this widely implemented approach. The Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of a Chronic Heart Failure (OPTIME-HF) trial did not show improved renal function with milrinone treatment [34]. The use of levosimendan, a cardiac calcium sensitizer that increases contractility not currently approved in the United States, was compared to dobutamine in the Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support (SURVIVE) trial, and there were no differences in rates of renal failure when the 2 groups were compared [35]. Nonetheless, if cardiac output is severely compromised, inotropes can be used for CRS1 treatment, but they should be used cautiously due the increased risks of lethal arrhythmias.

Dopamine

Use of low-dose dopamine to stimulate D1 and D2 receptors as a way to increase renal blood flow and promote increased glomerular filtration and urine production was extensively studied in ADHF. A small trial showed use of low dose dopamine had renal protective effects in a total of 20 patients [36]. However, when larger trials were conducted, such beneficial results were not consistently observed. The Dopamine in Acute Decompensated Heart Failure (DAD-HF I) trial compared low-dose furosemide plus low-dose dopamine (5 µg/kg/min) to high-dose furosemide alone in 60 patients. There were no differences in total diuresis, hospital stay, and 60-day mortality or rehospitalization rates, but there was a reduction in the renal dysfunction at the 24-hour time point in the dopamine-treated arm (6.7% versus 30%) [37]. The Dopamine in Acute Decompensated Heart Failure II trial randomized 161 ADHF patients to high-dose furosemide, low-dose furosemide and lose dose dopamine (5 µg/kg/min), or low-dose furosemide and assessed dyspnea, worsening renal function, length of stay, 60-day and one-year all-cause mortality and hospitalization for heart failure. Dopamine treatment did not improve any of the outcomes measured [38]. Finally, the most recent trial to examine the effects of dopamine was the Renal Optimization Strategies Evaluation (ROSE) trial. In this trial, there were 360 patients with ADHF randomized to nesiritide or dopamine versus placebo in a 2:1 design. When comparing dopamine (111 patients) treatment to placebo (115 patients), there were no differences in urine output, renal function as determined by cystatin C levels, or symptomatic improvements. However, there was more tachycardia in the dopamine group [39]. Currently, there is not strong evidence supporting routine use of dopamine in CRS1.

Nesiritide

Use of nesiritide, recombinant brain natriuretic peptide, was also investigated as a way to enhance urine production through the natriuretic effects of the peptide. The first attempt to explore this hypothesis was the B-Type Natriuretic Peptide in Cardiorenal Decompensation Syndrome (BNP-CARDS) trial. BNP-CARDS showed a 48-hour infusion of nesiritide (39 patients) or placebo (36 patients) in patients with ADHF and renal dysfunction (estimated GFR between 15–60 mL/min) did not reduce the incidence of worsening renal function as defined by a rise in serum creatinine by 20% [40]. A similar approach was implemented in the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial which examined over 7000 patients with ADHF. 3496 patients were treated with nesiritide and 3511 patients were treated with placebo for 24 hours and up to 7 days. Nesiritide treatment did not alter dyspnea at 6 and 24 hours, improve renal function as determined by creatinine change, or alter the combined end-point of rehospitalization or death 30 at days [41]. The ROSE trial examined the effects of nesiritide (117 patients) versus placebo (115 patients) for urine production, change in renal function as defined by change in cystatin C, and decongestion (urinary sodium excretion, weight change, and change in NT-proBNP) at 72 hours. Nesiritide did not alter any of the outcomes investigated [39]. Finally, a single-centered study conducted at the Mayo Clinic examined the effects of nesiritide (37 patients) or placebo (35 patients) with ADHF and pre-existing renal dysfunction (estimated GFR between 20 and 60 mL/min). These investigators found nesiritide treatment resulted in less renal dysfunction as measured by creatinine and BUN, but no changes in diuretic responsiveness, duration of hospitalization, or rehospitalization rates. Nesiritide did reduce serum endothelin levels, but had no effect on ANP, NT-pro BNP, renin, angiotensin II, or aldosterone [42]. In summary, nesiritide does not appear to have significant renal protective effects in ADHF.

Adenosine A1 Receptor Antagonists

The use of adenosine receptor antagonists to prevent adenosine-mediated vasoconstriction of renal vasculature in ADHF has also been examined. The first study conducted was a small double-blind randomized-controlled trial that investigated the effects of rolofylline, an adenosine A-1 antagonist, in patients with ADHF and an estimated creatinine clearance of 20-80 mL/min. The study had 27 patients in the placebo arm, 29 patients that received 2.5 mg of rolofylline, 31 patients received 15 mg of rolofylline, 30 patients received 30 mg of rolofylline, and 29 patients received 60 mg of rolofylline, all of which was daily for up to 3 days. Rolofylline treatment increased urine output on day 1 and improved renal function on day 2 [43]. These positive results led to the Placebo-Controlled Randomized Study of Selective Adenosine A1 Receptor Antagonist Rolofylline for Patients with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function (PROTECT) Trial. PROTECT assessed the effects of rolofylline (1356) or placebo (677) in patients with ADHF and an estimated creatinine clearance between 20 and 80 mL/min. There were no significant differences in renal function out to 14 days, but rolofylline led to more weight loss than placebo [44,45]. In a subgroup analysis of patients with severe baseline renal dysfunction (creatinine clearance of less than 30 mL/min), rolofylline reduced the combined 60-day end-point of hospitalization due to cardiovascular or renal cause and death [45]. Finally, the Effects of KW-3902 Injectable Emulsion on Heart Failure Signs and Symptoms, Diuresis, Renal Function, and Clinical Outcomes in Subjects Hospitalized with Worsening Renal Function and Heart Failure Requiring Intravenous Therapy (REACH-UP) trial probed the effects of rolofylline (36 patients) or placebo (40 patients) in patients with ADHF and renal impairment (creatinine clearance of 20-60 mL/min). Rolofylline treatment did not alter renal function, but there was a nonsignificant trend towards reduction in 60-day combined end-point of hospitalization due to renal or cardiovascular causes or death [46]. In summary, the use of rolofylline has not been conclusively associated with improved outcomes in CRS1.

Vasopressin Antagonists

The use of vasopressin antagonists to induce aquaphoresis and combat hyponatremia was studied in ADHF. Vasopressin antagonists were first investigated in the Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist (ACTIV) trial. ACTIV involved 3 doses of tolvaptan (78 patients received 30 mg, 84 patients received 60 mg, and 77 patients received 90 mg) versus placebo (80 patients), and tolvaptan increased urine production and decreased body weight compared to placebo without compromising renal function. A post-hoc analysis of patients with renal dysfunction (BUN > 29 mg/dL) and severe volume overload revealed a survival benefit at 60 days [47]. The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVERST) trial compared placebo (2061 patients) versus 30 mg/day of tolvaptan (2072 patients) within 48 hours after admission in an identical 2-trial design. Tolvaptan increased weight loss and reduced dyspnea acutely but did not alter all-cause mortality or cardiovascular or heart failure hospitalization rates out to 24 months post index hospitalization [48,49]. These data suggest vasopressin antagonists may potentiate diuresis acutely but likely do not improve long-term outcomes.

Corticosteroids

The use of corticosteroids in ADHF has been controversial as there were initial concerns that corticosteroids would increase fluid retention. However, corticosteroids augmented diuretic response and improved renal function in 13 ADHF patients who had inadequate response to sequential nephron blockage [50]. Furthermore, Zhang et al showed that prednisone treatment in 35 patients admitted with ADHF increased urinary volume, reduced dyspnea, reduced uric acid, and improved renal function [51]. These promising results led to the Cardiac Outcome Prevention Effectiveness of Glucocorticoids in Acute Decompensated Heart Failure (COPE-ADHF) trial. In this single-centered study, 102 patients with ADHF were randomized to either placebo [51] or corticosteroids [51] and the outcomes recorded included urinary volume, change in creatinine, and cardiovascular death at 30 days. Use of corticosteroids improved renal function, increased urine output, and reduced mortality (3/51 in corticosteroid group versus 10/51 in the placebo group) [52]. The mechanisms underlying the improvements with corticosteroids were not determined, but were hypothesized to be facilitation of natriuretic peptides or dilation of renal vasculature through activation of nitric oxide pathway or dopaminergic system.

Serelaxin

Serelaxin is a recombinantly expressed human relaxin-2, a peptide hormone present during pregnancy which facilitates physiological cardiovascular and renal adaptations [53–55], which showed potential benefits in CRS1. Analysis of the RELAX-AHF trial revealed serelaxin reduced incidence of worsening renal function at day 2 of treatment as defined by changes in serum creatinine, cystatin C, and BUN. Importantly, worsening renal function defined by cystatin C changes was associated with increased 180-day mortality in this analysis [56]. The mechanisms by which serelaxin prevented renal dysfunction are currently unknown as serelaxin treatment did not improve diuretic efficiency [19].

Ultrafiltration

Another treatment choice in CRS1 is mechanical removal of salt and water via ultrafiltration. Ultrafiltration showed early promise in Ultrafiltration Versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Heart Failure trial (UNLOAD) trial. In this study, 200 patients with ADHF were randomized to either ultrafiltration or medical management with loop diuretics. Use of ultrafiltration increased volume removal without any differences in renal function and reduced rehospitalization rates at 90 days [57].

However, when ultrafiltration was employed specifically in CRS1 patients in the Cardiorenal Rescue Study in Acute Decompensated Heart Failure trial (CARESS-HF), UF was not superior to medical treatment. There were 188 patients studied in CARESS-HF, and in the ultrafiltration arm there was increased risk of renal dysfunction, no differences in volume removal, and no change in rehospitalization rates at 90 days [58]. When trying to reconcile UNLOAD and CARESS-HF, the medical treatment arm in CARESS-HF was much more standardized and aggressive and UNLOAD was earlier implementation of ultrafiltration, which may have explained the differences. Interestingly, ultrafiltration was hypothesized to be advantageous over diuretic therapy through reduced activation of the renin-angiotensin-aldosterone system, but analysis of the patients from CARESS-HF showed higher levels of plasma renin activity and no difference in aldosterone levels in ultrafiltration patients [59].

Two meta-analyses have examined the use of ultrafiltration versus medical management in ADHF and both showed ultrafiltration was more effective in volume removal than medical therapy but did not improve rehospitalization or mortality rates [60,61]. This fact combined with the risks of vascular access placement and bleeding from anticoagulation limits to routine use of ultrafiltration in CRS1.

Continuous Renal Replacement Therapy

Once renal function deteriorates to the point that renal replacement therapy is needed for both volume removal and solute clearance in CRS1, continuous renal replacement therapy (CRRT) may be implemented. Unfortunately, there are few available data for this group of advanced CRS1 patients to guide physicians. There was a single-centered study conducted in Egypt that randomized 40 ADHF patients to either IV furosemide or CRRT. The patients treated with CRRT had greater weight loss and decreased length of stay in the ICU, but there were no differences in dialysis dependence rates or 30-day mortality [62]. Two single-centered studies reported outcomes associated with advanced CRS1 requiring CRRT. In a study conducted at the Cleveland Clinic, 63 patients with CRS1 were treated with ultrafiltration, of which 37 were converted to CRRT due to worsening renal function. Of the 37 patients treated with CRRT, 16 died in the hospital and 4 were discharged with hospice care [63]. In another retrospective study performed at the University of Alabama-Birmingham, use of rescue CRRT in advanced CRS1 was examined in 37 patients. 23 patients died during hospitalization and 2 were discharged to hospice care [64]. Combination of the Cleveland Clinic and University of Alabama-Birmingham studies revealed patients requiring CRRT in the setting of advanced CRS1 had an in-hospital mortality or palliative discharge rate of 60.8% (45/74). Clearly, this population needs further investigation to prevent such poor outcomes.

A summary of treatment approaches for CRS1 is presented in Table 3.

Future Treatment Options

Ongoing and Unreported Clinical Trials

Unfortunately, none of the current treatments for CRS1 have definitive improvements in outcomes, but there are several ongoing clinical trials which will hopefully identify novel treatment strategies. First of all, the Acetazolamide and Spironolactone to Increase Natriuresis in Congestive Heart Failure (Diuresis-CHF) trial is being conducted in Belgium. This study will examine the effects of acetazolamide with low dose diuretic versus high dose diuretics in one aim and the effects of upfront spironolactone in another. The outcomes analyzed will include total natriuresis, potassium homeostasis, NT-proBNP changes, change in renal function, peak serum levels of renin and aldosterone, weight change, urine volume, and change in edema (NCT01973335). The Protocolized Diuretic Strategy in Cardiorenal Failure (ProDius) trial is being performed at the University of Pittsburgh, and will determine the effects of a protocolized diuretic approach to target 3-5 liters of urine production a day versus standard therapy and will track the change in body weight, length of hospitalization, reshospitalization rates, mortality rates, venous compliance of internal jugular vein, clinical decongestion, change in renal function, and urine output (NCT01921829). The Levosimendan versus Dobutamine for Renal Function in Heart Failure (ELDOR) study is ongoing in Sweden and will probe the acute effects of levosimendan and dobutamine on renal perfusion. The endpoints will include changes in renal blood flow, GFR, renal vascular resistance, central hemodynamics, renal oxygen extraction and consumptions, and filtration fraction (NCT02133105). Finally, the Safety and Efficacy of Low Dose Hypertonic Saline and High Dose Furosemide for Congestive Heart Failure (REaCH) trial probed the effects of combination of hypertonic saline and furosemide versus furosemide in patients with ADHF and renal impairment defined by a GFR<60 mL/min. The outcomes were change in renal function, diuretic response, length of hospital stay, readmission rates, weight loss, BNP levels, and included a cost analysis. The study was completed but results are not currently available (NCT01028170)

Should Inflammation Be Targeted in CRS1?

Although proposed to play a role in the pathophysiology of CRS1, inflammation has not been explicitly targeted as a treatment for CRS1. One possible way to combat inflammation could be inhibition of the IL-6 pathway, which is support by preclinical work as previous studies showed IL-6 knockout mice were resistant to HgCl₂-induced renal injury and death [65] and IL-6 has negative inotropic effects in both isolated cardiomyocytes [66] and intact animals [67]. Thus, IL-6 antagonism may improve both cardiac and renal function, an ideal scenario for CRS1 patients. The availability of tocilizumab, an FDA-approved humanized antibody to the IL-6 receptor, may allow for investigation of this hypothesis in the future. Although not examined in the COPE-ADHF trial, an alternative explanation for the improvements associated with corticosteroids treatment were the anti-inflammatory effects. If this were true, corticosteroids would represent a relatively cheap treatment option for CRS1 patients, but more studies need to be conducted before this approach is widely implemented. Finally, use of cytokine profiling may be used to enrich a population of CRS1 patients that could be investigated in future clinical trials using anti-inflammatory medications.

Unanswered Questions Moving Forward

Severity of AKI and Treatment Effects

An important unknown that warrants further investigation is if the severity of AKI should dictate treatment choice in CRS1. As discussed above, increasing severity of AKI resulted in elevated risk of adverse events, but it remains unknown whether different treatments offer benefits for more or less severe renal impairment. Perhaps, future studies aimed at defining outcomes from different treatment strategies stratified by severity of renal dysfunction may reveal which patients benefit from the various treatment options for CRS1.

How Do We Best Define Renal Dysfunction in CRS1?

Currently, there is no accepted definition of renal dysfunction in CRS1. As discussed above, using the AKIN, KDIGO, or RIFLE scoring systems or diuretic responsiveness effectively differentiated outcomes in patients with CRS1. However, an agreed-upon definition would likely benefit the field going forward so this population could be systematically investigated in future studies.

Conclusion

In summary, CRS1 is a common clinical entity associated with poor patient outcomes. A complex pathophysiology marked by reduced cardiac output, increased central venous pressure, inflammation, and oxidative stress underlies the disease process. Unfortunately, no current treatment approach shows consistent improvements in outcomes, highlighting the urgent need for further research to reduce the burden that CRS1 imposes.

 

Corresponding author: Kurt W. Prins, MD, PhD, MMC 580 Mayo, 420 Delaware St SE, Minneapolis, MN 55455, [email protected].

Funding/support: Dr. Prins is funded by NIH F32 grant HL129554 and Dr. Thenappen is funded by AHA Scientist Development Grant 15SDG25560048.

From the Cardiovascular Division, Department of Internal Medicine, University of Minnesota, Minneapolis, MN.

 

Abstract

• Objective: To present a review of cardiorenal syndrome type 1 (CRS1).
• Methods: Review of the literature.
• Results: Acute kidney injury occurs in approximately one-third of patients with acute decompensated heart failure (ADHF) and the resultant condition was named CRS1. A growing body of literature shows CRS1 patients are at high risk for poor outcomes, and thus there is an urgent need to understand the pathophysiology and subsequently develop effective treatments. In this review we discuss prevalence, proposed pathophysiology including hemodynamic and nonhemodynamic factors, prognosticating variables, data for different treatment strategies, and ongoing clinical trials and highlight questions and problems physicians will face moving forward with this common and challenging condition.
• Conclusion: Further research is needed to understand the pathophysiology of this complex clinical entity and to develop effective treatments.

 

Acute decompensated heart failure (ADHF) is an epidemic facing physicians throughout the world. In the United States alone, ADHF accounts for over 1 million hospitalizations annually, with costs in 2012 reaching $30.7 billion [1]. Despite the advances in chronic heart failure management, ADHF continues to be associated with poor outcomes as exemplified by 30-day readmission rates of over 20% and in-hospital mortality rates of 5% to 6%, both of which have not significantly improved over the past 20 years [2,3]. One of the strongest predictors of adverse outcomes in ADHF is renal dysfunction. An analysis from the Acute Decompensated Heart Failure National Registry (ADHERE) revealed the combination of renal dysfunction (creatinine > 2.75 mg/dL and blood urea nitrogen (BUN) > 43 mg/dL) and hypotension (systolic blood pressure (SBP) < 115 mm Hg) upon admission was associated with an in-hospital mortality of > 20% [4]. The Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) registry documented a 16.3% in-hospital mortality when patients had a SBP < 100 mm Hg and creatinine > 2.0 mg/dL at admission [5].

The presence of acute kidney injury in the setting of ADHF is a very common occurrence and was termed cardiorenal syndrome type 1 (CRS1) [6]. The prevalence of CRS1 in single-centered studies ranged from 32% to 40% of all ADHF admissions [7,8]. If this estimate holds true throughout the United States, there would be 320,000 to 400,000 hospitalizations for CRS1 annually, highlighting the magnitude of this problem. Moreover, with the number of patients with heart failure expected to continue to rise, CRS1 will only become more prevalent in the future. In this review we discuss the prevalence, proposed pathophysiology including hemodynamic and nonhemodynamic factors, prognosticating variables, data for different treatment strategies, ongoing clinical trials, and highlight questions and problems physicians will face moving forward in this common and challenging condition.

Pathogenesis of CRS1

Hemodynamic Effects

The early hypothesis for renal dysfunction in ADHF centered on hemodynamics, as reduced cardiac output was believed to decrease renal perfusion. However, analysis of invasive hemodynamics from patients with ADHF suggested that central venous pressure (CVP) was actually a better predictor of the development of CRS1 than cardiac output. In a single-center study conducted at the Cleveland Clinic, hemodynamics from 145 patients with ADHF were evaluated and surprisingly baseline cardiac index was greater in the patients with CRS1 than patients without renal dysfunction (2.0 ± 0.8 L/min/m² vs 1.8 ± 0.4 L/min/m²; P = 0.008). However, baseline CVP was higher in the CRS1 group (18 ± 7 mm Hg vs 12 ± 6 mm Hg; P = 0.001), and there was a heightened risk of developing CRS1 as CVP increased. In fact, 75% of the patients with a CVP of > 24 mm Hg developed renal impairment [9]. In a retrospective study of the Evaluation Study of Congestive Heart Failure and Pulmonary Arterial Catheter Effectiveness (ESCAPE) trial, the only hemodynamic parameter that correlated with baseline creatinine was CVP. However, no invasive measures predicted worsening renal function during hospitalization [10]. Finally, an experiment that used isolated canine kidneys showed increased venous pressure acutely reduced urine production. Interestingly, this relationship was dependent on arterial pressure; as arterial flow decreased smaller increases in CVP were needed to reduce urine output [11]. Together, these data suggest increased CVP plays an important role in CRS1, but imply hemodynamics alone may not fully explain the pathophysiology of CRS1.

Inflammation

As information about how hemodynamics incompletely predict renal dysfunction in ADHF became available, alternative hypotheses were investigated to gain a deeper understanding of the pathophysiology underlying CRS1. A pathological role of inflammation in CRS1 has gained attention due to recent publications. First of all, serum levels of the pro-inflammatory cytokines TNF-a and IL-6 were elevated in patients with CRS1 when compared to health controls [12]. Interestingly, Virzi et al showed that the median value of IL-6 was 5 times higher in CRS1 patients when compared to ADHF patients without renal dysfunction [13]. The negative consequences of elevated serum cytokines were demonstrated when incubation of a human cell line of monocytes with serum from CRS1 patients induced apoptosis in 81% of cells compared to just 11% of cells with control serum [12]. It is possible that cytokine-induced apoptosis could occur in other cell types in different organs in patients with CRS1, which may contribute to both cardiac and renal dysfunction. Finally, analysis from a rat model of CRS1 revealed macrophage infiltration into the kidneys and increased numbers of activated monocytes in the peripheral blood. Interestingly, monocyte/macrophage depletion using liposome clodronate prevented chronic renal dysfunction in the rat model [14]. In summary, these data suggest inflammation contributes to CRS1 pathophysiology, but more experimental data is needed to determine if there is a causal relationship.

Oxidative Stress

Very recently, oxidative stress was proposed to play a role in CRS1. Virzi et al analyzed serum levels of markers of oxidative stress and compared ADHF patients without renal impairment to CRS1 patients. The markers of oxidative stress, which included myeloperoxidase, nitric oxide, copper/zinc superoxide dismutase, and endogenous peroxidase, were all significantly higher in CRS1 patients [13]. While provocative, the tissues responsible for the generation of these molecules and the subsequent effects have not yet been fully elucidated.

The proposed pathophysiology is seen in the Figure.

Prognostication

Severity of Acute Kidney Injury

Initial publications did not document a strong link between kidney injury and poor outcomes in ADHF. Firstly, Ather et al performed a single-centered study that investigated how change in renal function defined by change in creatinine, estimated GFR, and BUN affected outcomes one year post admission for ADHF. Kidney injury defined by a change in creatinine or in estimated GFR was not associated with increased risk of mortality, but a change in BUN was associated with increased mortality in a univariate analysis [15]. Testani et al retrospectively analyzed patients from the ESCAPE trial and found worsening renal function defined by a ≥ 20% reduction in estimated GFR was not significantly associated with 180-day mortality, but there was a trend towards higher mortality (hazard ration 1.4; P = 0.11) [16]. Importantly, neither of 2 these studies assessed how severity of AKI impacted outcomes, which may have contributed to the weak relationships observed.

However, when AKI severity in CRS1 was quantified, poor outcomes were more likely as AKI severity increased. Firstly, Roy et al determined how AKI impacted adverse events (mortality, rehospitalization, or need for dialysis) rates in 637 patients with ADHF. Severity of AKI was quantified using RIFLE, AKIN, and KDIGO guidelines (Table 1), and the authors found that as the severity of renal injury increased, the likelihood of an adverse event was higher. In fact, the most severe AKI grade using all 3 AKI grading systems resulted in an odds ratio ranging from 45.3 to 101.6 for an adverse event at 30 days when compared to no kidney injury [7]. Hata et al documented that AKI (defined using RIFLE criteria) in ADHF resulted in a longer ICU stay, total hospital length of stay, and higher in-hospital mortality rates, and patients with a failure-grade AKI had in-hospital mortality rate of 49.1% [17]. Finally, Li et al evaluated AKI in 1005 patients with ADHF and showed that AKI defined by RIFLE, AKIN, or KDIGO methods increased risk of in-hospital mortality, and that a KDIGO grade 3 AKI was associated with a 35.5% in-hospital mortality rate [8]. These data indicate CRS1 is associated with poor outcomes, and there is a heightened risk of adverse events as AKI severity increases.

Diuretic Responsiveness

Using change in serum creatinine as a marker of renal impairment may not be the best choice for predicting outcomes in CRS1 because the lab values are not a real-time measure of kidney function and serum creatinine can be affected by both body mass and pharmaceutical agents. Therefore, the prognosticating ability of urine production relative to diuretic dose as a surrogate measure of renal function in ADHF was investigated by several groups (Table 2). Testani et al examined urine output per 40 mg of furosemide and tracked outcomes in 2 cohorts: patients admitted with ADHF at the University of Pennsylvania (657 patients) and patients from the ESCAPE trial (390 patients). Patients were split into high responders or low responders based on the median value. In both of the patient cohorts, low diuretic efficiency was associated with increased mortality using a multivariate model (hazard ratio of 1.36 in the Penn patients and 2.86 in the ESCAPE patients). The combination of low diuretic efficiency and high diuretic dose (> 280 mg in the Penn cohort and > 240 mg in the ESCAPE cohort) resulted in the worst prognosis, with mortality rates of approximately 70% at 6 years in the Penn cohort and approximately 35% at 180 days in the ESCAPE cohort [18].

Voors et al performed a retrospective analysis of diuretic responsiveness in 1161 patients from the Relaxin in Acute Heart Failure (RELAX-AHF) trial. Diuretic responsiveness was defined as weight change (kg) per diuretic dose (IV furosemide and PO furosemide) over 5 days and then patients were separated into tertiles. The lowest tertile group had an approximate 20% incidence of 60-day combined end-point of death, heart failure or renal failure readmission compared to less than 10% incidence in the middle and upper tertiles. Interestingly, when the effects of worsening renal function (WRF), defined as creatinine change of ≥ 0.3 mg/dL, were examined in patients stratified by diuretic response, WRF did not offer additional prognostic information [19].

Finally, Valenete et al analyzed diuretic response in 1745 patients from the PROTECT trial (Placebo-Controlled Randomized Study of the Selective A1-Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function). Diuretic response was calculated using the weight change per 40 mg of furosemide, and as diuretic response declined there was increasing risk of 60-day rehospitalization and 180-day mortality rates. In fact, the lowest quintile responders had a 25% mortality rate at 180 days [20].

Emerging Biomarkers

Urine Neutrophil Gelatinase-Associated Lipocalin

Because previous studies showed urinary levels of NGAL was an earlier and more reliable marker of renal dysfunction than creatinine in AKI [21], it was studied as a possible biomarker for the development of CRS1 in ADHF. A single-centered study quantified levels of urine NGAL in 100 patients admitted with heart failure and then tracked the rates of acute kidney injury. Urine NGAL was elevated in patients that developed AKI and a cut-off value 12 ng/mL had a sensitivity of 79% and specificity of 67% for predicting CRS1 [22]. While promising, further studies are needed to better define the role of NGAL in CRS1.

Cystatin C

Cystatin C is a ubiquitously expressed cysteine protease that has a constant production rate and is freely filtered by the glomerulus without being secreted into the tubules, and has effectively prognosticated outcomes in ADHF [23]. Lassus et al showed an adjusted hazard ratio of 3.2 (2.0–5.3) for 12-month mortality when cystatin C levels were elevated. Moreover, patients with the highest tertitle of NT-proBNP and cystatin C had a 48.7% 1-year mortality. Interestingly, patients with an elevated cystatin C but normal creatinine had a 40.6% 1-year mortality compared to 12.6% for those with normal cystatin C and creatinine [24]. Furthermore, Arimoto et al showed elevated cystatin C predicted death or rehospitalization in a small cohort of ADHF patients in Japan [25]. Also, Naruse et al showed cystatin C was a better predictor of cardiac death than estimated GFR by the Modification of Diet in Renal Disease Study (MDRD) equation [26]. Finally, Manzano-Fernandez et al showed the highest tertile of cystatin C was a significant independent risk factor for 2-year death or rehospitalization while creatinine and MDRD estimates of GFR were not [27]. In agreement with Lassus et al, elevations in either 2 or 3 of cystatin C, troponin, and NT-proBNP predicted death or rehospitalization when compared to those with normal levels of these 3 markers [27]. In conclusion, cystatin C either alone or in combination with other biomarkers identifies high-risk patients.

Kidney Injury Molecule 1

Kidney injury molecule 1 (KIM-1) is a type-1 cell membrane glycoprotein expressed in regenerating proximal tubular cells but not under normal conditions [28]. Although associated with increased risk of hospitalization and mortality in chronic heart failure [29,30], elevated levels of urinary KIM-1 did not predict mortality in ADHF [31]. Further studies are needed to elucidate the utility of KIM-1 in CRS1.

Treatment Approaches

Diuretics

Loop diuretics are the main treatment for decongestion of patients with CRS1. To date, no clinical trial has compared the different loop diuretics (furosemide, bumetanide, torsemide, or ethacrynic acid) to each other, so there is no clear choice of which loop diuretic is the best. However, dosing scheme was investigated in the Dose Optimization Strategies Evaluation (DOSE) trial. In this trial, 308 patients were randomized in a 1:1:1:1 design in which patients were placed in groups with low-dose (equivalent to oral dose) or high-dose (2.5 times oral dose) intermittent parental therapy or alternatively low-dose or high-dose continuous drip therapy. There were no differences in dyspnea, fluid changes, change in creatinine, hospital length stay, or rehospitalization and death rates when the intermittent and drip approaches were compared. However, the high-dose arm had decreased dyspnea, increased volume removal, but there were more occurrences of AKIs when compared to the low-dose arm [32].

In clinical practice, if loop diuretic treatment does not result in the desired urine output, a second-site diuretic may be added to potentiate diuresis. Unfortunately, there is little data on this common clinical practice and thus the optimal choice of second site agent (chlorthiazide or metolazone) is unknown. Frequently, the deciding factor is based upon cost or concern that oral absorption of metolazone will be ineffective. However, Moranville et al recently performed a retrospective assessment comparing chlorthiazide (22 patients) to metolazone (33 patients) in ADHF patients with renal dysfunction defined by a creatinine clearance of 15–50 mL/min. There was a nonsignificant trend towards increased urine output in the metolazone group, no differences in the rates of adverse events, and the chlorthiazide group actually had a longer hospital stay [33]. While potentially promising results, the retrospective nature of the study made it difficult to determine if the differences were due to treatment approach or dissimilarities of patient illness. Nonetheless, physicians must remain vigilant when implementing the second-site diuretic approach because it can lead to marked diuretic response leading to metabolic derangements including hypokalemia, hyponatremia, hypomagnesaemia, and metabolic alkalosis.

Inotropes

The use of inotropic agents such as dobutamine or milrinone can be used to augment cardiac function when there is a known low-output state for better renal perfusion in CRS1. Unfortunately, there is little objective data available about the utility of this widely implemented approach. The Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of a Chronic Heart Failure (OPTIME-HF) trial did not show improved renal function with milrinone treatment [34]. The use of levosimendan, a cardiac calcium sensitizer that increases contractility not currently approved in the United States, was compared to dobutamine in the Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support (SURVIVE) trial, and there were no differences in rates of renal failure when the 2 groups were compared [35]. Nonetheless, if cardiac output is severely compromised, inotropes can be used for CRS1 treatment, but they should be used cautiously due the increased risks of lethal arrhythmias.

Dopamine

Use of low-dose dopamine to stimulate D1 and D2 receptors as a way to increase renal blood flow and promote increased glomerular filtration and urine production was extensively studied in ADHF. A small trial showed use of low dose dopamine had renal protective effects in a total of 20 patients [36]. However, when larger trials were conducted, such beneficial results were not consistently observed. The Dopamine in Acute Decompensated Heart Failure (DAD-HF I) trial compared low-dose furosemide plus low-dose dopamine (5 µg/kg/min) to high-dose furosemide alone in 60 patients. There were no differences in total diuresis, hospital stay, and 60-day mortality or rehospitalization rates, but there was a reduction in the renal dysfunction at the 24-hour time point in the dopamine-treated arm (6.7% versus 30%) [37]. The Dopamine in Acute Decompensated Heart Failure II trial randomized 161 ADHF patients to high-dose furosemide, low-dose furosemide and lose dose dopamine (5 µg/kg/min), or low-dose furosemide and assessed dyspnea, worsening renal function, length of stay, 60-day and one-year all-cause mortality and hospitalization for heart failure. Dopamine treatment did not improve any of the outcomes measured [38]. Finally, the most recent trial to examine the effects of dopamine was the Renal Optimization Strategies Evaluation (ROSE) trial. In this trial, there were 360 patients with ADHF randomized to nesiritide or dopamine versus placebo in a 2:1 design. When comparing dopamine (111 patients) treatment to placebo (115 patients), there were no differences in urine output, renal function as determined by cystatin C levels, or symptomatic improvements. However, there was more tachycardia in the dopamine group [39]. Currently, there is not strong evidence supporting routine use of dopamine in CRS1.

Nesiritide

Use of nesiritide, recombinant brain natriuretic peptide, was also investigated as a way to enhance urine production through the natriuretic effects of the peptide. The first attempt to explore this hypothesis was the B-Type Natriuretic Peptide in Cardiorenal Decompensation Syndrome (BNP-CARDS) trial. BNP-CARDS showed a 48-hour infusion of nesiritide (39 patients) or placebo (36 patients) in patients with ADHF and renal dysfunction (estimated GFR between 15–60 mL/min) did not reduce the incidence of worsening renal function as defined by a rise in serum creatinine by 20% [40]. A similar approach was implemented in the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial which examined over 7000 patients with ADHF. 3496 patients were treated with nesiritide and 3511 patients were treated with placebo for 24 hours and up to 7 days. Nesiritide treatment did not alter dyspnea at 6 and 24 hours, improve renal function as determined by creatinine change, or alter the combined end-point of rehospitalization or death 30 at days [41]. The ROSE trial examined the effects of nesiritide (117 patients) versus placebo (115 patients) for urine production, change in renal function as defined by change in cystatin C, and decongestion (urinary sodium excretion, weight change, and change in NT-proBNP) at 72 hours. Nesiritide did not alter any of the outcomes investigated [39]. Finally, a single-centered study conducted at the Mayo Clinic examined the effects of nesiritide (37 patients) or placebo (35 patients) with ADHF and pre-existing renal dysfunction (estimated GFR between 20 and 60 mL/min). These investigators found nesiritide treatment resulted in less renal dysfunction as measured by creatinine and BUN, but no changes in diuretic responsiveness, duration of hospitalization, or rehospitalization rates. Nesiritide did reduce serum endothelin levels, but had no effect on ANP, NT-pro BNP, renin, angiotensin II, or aldosterone [42]. In summary, nesiritide does not appear to have significant renal protective effects in ADHF.

Adenosine A1 Receptor Antagonists

The use of adenosine receptor antagonists to prevent adenosine-mediated vasoconstriction of renal vasculature in ADHF has also been examined. The first study conducted was a small double-blind randomized-controlled trial that investigated the effects of rolofylline, an adenosine A-1 antagonist, in patients with ADHF and an estimated creatinine clearance of 20-80 mL/min. The study had 27 patients in the placebo arm, 29 patients that received 2.5 mg of rolofylline, 31 patients received 15 mg of rolofylline, 30 patients received 30 mg of rolofylline, and 29 patients received 60 mg of rolofylline, all of which was daily for up to 3 days. Rolofylline treatment increased urine output on day 1 and improved renal function on day 2 [43]. These positive results led to the Placebo-Controlled Randomized Study of Selective Adenosine A1 Receptor Antagonist Rolofylline for Patients with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function (PROTECT) Trial. PROTECT assessed the effects of rolofylline (1356) or placebo (677) in patients with ADHF and an estimated creatinine clearance between 20 and 80 mL/min. There were no significant differences in renal function out to 14 days, but rolofylline led to more weight loss than placebo [44,45]. In a subgroup analysis of patients with severe baseline renal dysfunction (creatinine clearance of less than 30 mL/min), rolofylline reduced the combined 60-day end-point of hospitalization due to cardiovascular or renal cause and death [45]. Finally, the Effects of KW-3902 Injectable Emulsion on Heart Failure Signs and Symptoms, Diuresis, Renal Function, and Clinical Outcomes in Subjects Hospitalized with Worsening Renal Function and Heart Failure Requiring Intravenous Therapy (REACH-UP) trial probed the effects of rolofylline (36 patients) or placebo (40 patients) in patients with ADHF and renal impairment (creatinine clearance of 20-60 mL/min). Rolofylline treatment did not alter renal function, but there was a nonsignificant trend towards reduction in 60-day combined end-point of hospitalization due to renal or cardiovascular causes or death [46]. In summary, the use of rolofylline has not been conclusively associated with improved outcomes in CRS1.

Vasopressin Antagonists

The use of vasopressin antagonists to induce aquaphoresis and combat hyponatremia was studied in ADHF. Vasopressin antagonists were first investigated in the Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist (ACTIV) trial. ACTIV involved 3 doses of tolvaptan (78 patients received 30 mg, 84 patients received 60 mg, and 77 patients received 90 mg) versus placebo (80 patients), and tolvaptan increased urine production and decreased body weight compared to placebo without compromising renal function. A post-hoc analysis of patients with renal dysfunction (BUN > 29 mg/dL) and severe volume overload revealed a survival benefit at 60 days [47]. The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVERST) trial compared placebo (2061 patients) versus 30 mg/day of tolvaptan (2072 patients) within 48 hours after admission in an identical 2-trial design. Tolvaptan increased weight loss and reduced dyspnea acutely but did not alter all-cause mortality or cardiovascular or heart failure hospitalization rates out to 24 months post index hospitalization [48,49]. These data suggest vasopressin antagonists may potentiate diuresis acutely but likely do not improve long-term outcomes.

Corticosteroids

The use of corticosteroids in ADHF has been controversial as there were initial concerns that corticosteroids would increase fluid retention. However, corticosteroids augmented diuretic response and improved renal function in 13 ADHF patients who had inadequate response to sequential nephron blockage [50]. Furthermore, Zhang et al showed that prednisone treatment in 35 patients admitted with ADHF increased urinary volume, reduced dyspnea, reduced uric acid, and improved renal function [51]. These promising results led to the Cardiac Outcome Prevention Effectiveness of Glucocorticoids in Acute Decompensated Heart Failure (COPE-ADHF) trial. In this single-centered study, 102 patients with ADHF were randomized to either placebo [51] or corticosteroids [51] and the outcomes recorded included urinary volume, change in creatinine, and cardiovascular death at 30 days. Use of corticosteroids improved renal function, increased urine output, and reduced mortality (3/51 in corticosteroid group versus 10/51 in the placebo group) [52]. The mechanisms underlying the improvements with corticosteroids were not determined, but were hypothesized to be facilitation of natriuretic peptides or dilation of renal vasculature through activation of nitric oxide pathway or dopaminergic system.

Serelaxin

Serelaxin is a recombinantly expressed human relaxin-2, a peptide hormone present during pregnancy which facilitates physiological cardiovascular and renal adaptations [53–55], which showed potential benefits in CRS1. Analysis of the RELAX-AHF trial revealed serelaxin reduced incidence of worsening renal function at day 2 of treatment as defined by changes in serum creatinine, cystatin C, and BUN. Importantly, worsening renal function defined by cystatin C changes was associated with increased 180-day mortality in this analysis [56]. The mechanisms by which serelaxin prevented renal dysfunction are currently unknown as serelaxin treatment did not improve diuretic efficiency [19].

Ultrafiltration

Another treatment choice in CRS1 is mechanical removal of salt and water via ultrafiltration. Ultrafiltration showed early promise in Ultrafiltration Versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Heart Failure trial (UNLOAD) trial. In this study, 200 patients with ADHF were randomized to either ultrafiltration or medical management with loop diuretics. Use of ultrafiltration increased volume removal without any differences in renal function and reduced rehospitalization rates at 90 days [57].

However, when ultrafiltration was employed specifically in CRS1 patients in the Cardiorenal Rescue Study in Acute Decompensated Heart Failure trial (CARESS-HF), UF was not superior to medical treatment. There were 188 patients studied in CARESS-HF, and in the ultrafiltration arm there was increased risk of renal dysfunction, no differences in volume removal, and no change in rehospitalization rates at 90 days [58]. When trying to reconcile UNLOAD and CARESS-HF, the medical treatment arm in CARESS-HF was much more standardized and aggressive and UNLOAD was earlier implementation of ultrafiltration, which may have explained the differences. Interestingly, ultrafiltration was hypothesized to be advantageous over diuretic therapy through reduced activation of the renin-angiotensin-aldosterone system, but analysis of the patients from CARESS-HF showed higher levels of plasma renin activity and no difference in aldosterone levels in ultrafiltration patients [59].

Two meta-analyses have examined the use of ultrafiltration versus medical management in ADHF and both showed ultrafiltration was more effective in volume removal than medical therapy but did not improve rehospitalization or mortality rates [60,61]. This fact combined with the risks of vascular access placement and bleeding from anticoagulation limits to routine use of ultrafiltration in CRS1.

Continuous Renal Replacement Therapy

Once renal function deteriorates to the point that renal replacement therapy is needed for both volume removal and solute clearance in CRS1, continuous renal replacement therapy (CRRT) may be implemented. Unfortunately, there are few available data for this group of advanced CRS1 patients to guide physicians. There was a single-centered study conducted in Egypt that randomized 40 ADHF patients to either IV furosemide or CRRT. The patients treated with CRRT had greater weight loss and decreased length of stay in the ICU, but there were no differences in dialysis dependence rates or 30-day mortality [62]. Two single-centered studies reported outcomes associated with advanced CRS1 requiring CRRT. In a study conducted at the Cleveland Clinic, 63 patients with CRS1 were treated with ultrafiltration, of which 37 were converted to CRRT due to worsening renal function. Of the 37 patients treated with CRRT, 16 died in the hospital and 4 were discharged with hospice care [63]. In another retrospective study performed at the University of Alabama-Birmingham, use of rescue CRRT in advanced CRS1 was examined in 37 patients. 23 patients died during hospitalization and 2 were discharged to hospice care [64]. Combination of the Cleveland Clinic and University of Alabama-Birmingham studies revealed patients requiring CRRT in the setting of advanced CRS1 had an in-hospital mortality or palliative discharge rate of 60.8% (45/74). Clearly, this population needs further investigation to prevent such poor outcomes.

A summary of treatment approaches for CRS1 is presented in Table 3.

Future Treatment Options

Ongoing and Unreported Clinical Trials

Unfortunately, none of the current treatments for CRS1 have definitive improvements in outcomes, but there are several ongoing clinical trials which will hopefully identify novel treatment strategies. First of all, the Acetazolamide and Spironolactone to Increase Natriuresis in Congestive Heart Failure (Diuresis-CHF) trial is being conducted in Belgium. This study will examine the effects of acetazolamide with low dose diuretic versus high dose diuretics in one aim and the effects of upfront spironolactone in another. The outcomes analyzed will include total natriuresis, potassium homeostasis, NT-proBNP changes, change in renal function, peak serum levels of renin and aldosterone, weight change, urine volume, and change in edema (NCT01973335). The Protocolized Diuretic Strategy in Cardiorenal Failure (ProDius) trial is being performed at the University of Pittsburgh, and will determine the effects of a protocolized diuretic approach to target 3-5 liters of urine production a day versus standard therapy and will track the change in body weight, length of hospitalization, reshospitalization rates, mortality rates, venous compliance of internal jugular vein, clinical decongestion, change in renal function, and urine output (NCT01921829). The Levosimendan versus Dobutamine for Renal Function in Heart Failure (ELDOR) study is ongoing in Sweden and will probe the acute effects of levosimendan and dobutamine on renal perfusion. The endpoints will include changes in renal blood flow, GFR, renal vascular resistance, central hemodynamics, renal oxygen extraction and consumptions, and filtration fraction (NCT02133105). Finally, the Safety and Efficacy of Low Dose Hypertonic Saline and High Dose Furosemide for Congestive Heart Failure (REaCH) trial probed the effects of combination of hypertonic saline and furosemide versus furosemide in patients with ADHF and renal impairment defined by a GFR<60 mL/min. The outcomes were change in renal function, diuretic response, length of hospital stay, readmission rates, weight loss, BNP levels, and included a cost analysis. The study was completed but results are not currently available (NCT01028170)

Should Inflammation Be Targeted in CRS1?

Although proposed to play a role in the pathophysiology of CRS1, inflammation has not been explicitly targeted as a treatment for CRS1. One possible way to combat inflammation could be inhibition of the IL-6 pathway, which is support by preclinical work as previous studies showed IL-6 knockout mice were resistant to HgCl₂-induced renal injury and death [65] and IL-6 has negative inotropic effects in both isolated cardiomyocytes [66] and intact animals [67]. Thus, IL-6 antagonism may improve both cardiac and renal function, an ideal scenario for CRS1 patients. The availability of tocilizumab, an FDA-approved humanized antibody to the IL-6 receptor, may allow for investigation of this hypothesis in the future. Although not examined in the COPE-ADHF trial, an alternative explanation for the improvements associated with corticosteroids treatment were the anti-inflammatory effects. If this were true, corticosteroids would represent a relatively cheap treatment option for CRS1 patients, but more studies need to be conducted before this approach is widely implemented. Finally, use of cytokine profiling may be used to enrich a population of CRS1 patients that could be investigated in future clinical trials using anti-inflammatory medications.

Unanswered Questions Moving Forward

Severity of AKI and Treatment Effects

An important unknown that warrants further investigation is if the severity of AKI should dictate treatment choice in CRS1. As discussed above, increasing severity of AKI resulted in elevated risk of adverse events, but it remains unknown whether different treatments offer benefits for more or less severe renal impairment. Perhaps, future studies aimed at defining outcomes from different treatment strategies stratified by severity of renal dysfunction may reveal which patients benefit from the various treatment options for CRS1.

How Do We Best Define Renal Dysfunction in CRS1?

Currently, there is no accepted definition of renal dysfunction in CRS1. As discussed above, using the AKIN, KDIGO, or RIFLE scoring systems or diuretic responsiveness effectively differentiated outcomes in patients with CRS1. However, an agreed-upon definition would likely benefit the field going forward so this population could be systematically investigated in future studies.

Conclusion

In summary, CRS1 is a common clinical entity associated with poor patient outcomes. A complex pathophysiology marked by reduced cardiac output, increased central venous pressure, inflammation, and oxidative stress underlies the disease process. Unfortunately, no current treatment approach shows consistent improvements in outcomes, highlighting the urgent need for further research to reduce the burden that CRS1 imposes.

 

Corresponding author: Kurt W. Prins, MD, PhD, MMC 580 Mayo, 420 Delaware St SE, Minneapolis, MN 55455, [email protected].

Funding/support: Dr. Prins is funded by NIH F32 grant HL129554 and Dr. Thenappen is funded by AHA Scientist Development Grant 15SDG25560048.

 

Case

A 39-year-old woman presented to the ED with a chief complaint of intermittent right flank pain that radiated into her groin area. She stated the pain had begun suddenly, 4 hours prior to arrival, and was accompanied by nausea and vomiting. The patient said that she had taken acetaminophen for the pain, but had received no relief. Regarding history, according to the patient, her last menstrual period ended 2 days earlier. She denied any urinary symptoms, diarrhea, or constipation. She had no history of abdominal surgery and was currently not on any medications.

The patient’s vital signs at presentation were: temperature 98.7°F; blood pressure, 130/90 mm Hg; heart rate, 110 beats/minute; and respiratory rate, 18 breaths/minute. Oxygen saturation was 98% on room air. On physical examination, she appeared to be in mild distress, pacing around the room. There was moderate right costovertebral tenderness on percussion; the abdomen was soft and nontender.

  

 

Incidence

As ED visits for nephrolithiasis are increasing, so too are the health-care costs associated with this condition. Between 1992 and 2009, emergent-care presentations for nephrolithiasis rose from 178 to 340 visits per 100,000 individuals.¹ Approximately 1 in 11 people in the United States will be affected by nephrolithiasis during their lifetime.² Estimated health-care costs associated with these complaints were roughly $2 billion in 2000—an increase of 50% since 1994.²

  

 

Evaluation and Diagnosis

Laboratory Evaluation
Urinalysis is one of the initial studies for patients with suspected nephrolithiasis. Although hematuria is a classic finding associated with renal calculi, its sensitivity on microscopic analysis is around 84%. Therefore, the absence of hematuria does not exclude renal colic in the differential diagnosis.³

In addition to detecting hematuria, urinalysis can also reveal an underlying infection. One study by Abrahamian et al⁴ found that roughly 8% of patients presenting with acute nephrolithiasis had a urinary tract infection (UTI)—many without any clinical findings of infection. The presence of pyuria, however, has only moderate accuracy in identifying UTIs in patients with kidney stones.⁴ If an infected stone cannot be excluded clinically, computed tomography (CT) is indicated.

Mild leukocytosis (ie, <15,000 cells/mcL) is another common finding in patients with acute renal colic.⁵ A leukocyte count >15,000 cells/mcL is suspicious for infection or other pathology. A blood-chemistry panel to evaluate renal function is appropriate as a baseline—particularly for patients in whom treatment with a nonsteroidal anti-inflammatory (NSAID) drug is anticipated.

Unenhanced Computed Tomography
With the ability to visualize renal calculi (Figure 1), the use of noncontrast CT has become a standard initial imaging modality in assessing patients with renal colic. Between 1992 and 2009, the use of CT to evaluate patients presenting with flank pain for suspected renal colic more than tripled from 21% to 71%.⁶ An analysis performed by the American College of National Radiology Data Registry⁷ shows the mean radiation dose given by institutions for renal colic CT is unnecessarily high, and that few institutions follow CT-stone protocols aimed at minimizing radiation exposure while still maintaining proper diagnostic accuracy. A typical CT of the abdomen and pelvis is equivalent to over 100 two-view chest X-rays.⁸ Though controversial, data from a white paper by the American College of Radiology suggest that the ionizing radiation exposure from just one CT for renal colic causes an increase in lifetime cancer risk.⁹

Despite the increase in CT imaging to evaluate patients presenting to the ED with nephrolithiasis/flank pain, the proportion of patients diagnosed with a kidney stone remained the same between 2000 and 2008, with no significant change in outcomes.^10-12 Moreover, the use of CT as an initial imaging modality in patients presenting with flank pain—but with no sign of infection—is unlikely to reveal important alternative findings.¹³

Regarding the sensitivity of CT in detecting nephrolithiasis, one study demonstrates a sensitivity of 100% and a specificity of 94% for noncontrast CT.¹⁴ Controversy, however, still exists regarding the necessity and utility of CT in diagnosing nephrolithiasis,¹⁵ and CT is one of the top 10 tests included in the American College of Emergency Physicians (ACEP) 2014 Choosing Wisely campaign. In this campaign, ACEP recommended emergency physicians (EPs) avoid abdominal and pelvic CT in otherwise healthy patients younger than age 50 years who present with symptoms consistent with uncomplicated renal colic and who have a known history of nephrolithiasis or ureterolithiasis.¹⁵ The ACEP also noted that CTs in this context do not often change treatment decisions and are associated with unnecessary radiation exposure and cost.¹⁵

While keeping the aforementioned recommendations in mind, if an EP intends to refer a renal colic patient to a urologist a CT scan is necessary either in the ED or as an outpatient. In all cases (except perhaps in patients in whom there is a history of renal stones), the urologist will need this study to determine the size and location of the stone in order to provide recommendations for management.

Ultrasound

Ultrasound is another imaging modality with a high sensitivity in detecting renal calculi (Figure 2), and its role in the diagnosis of nephrolithiasis continues to evolve. A study by Smith-Bindman et al¹⁶ showed that in ED patients with symptoms suggestive of kidney stones, ultrasound as the initial imaging study was associated with lower cumulative radiation exposure than CT alone, with no significant differences in high-risk diagnosis with complications, serious adverse events, pain scores, return ED visits, or hospitalizations. In this study, 40% of patients who received point-of-care (POC) ultrasound and 27% who received radiology ultrasound subsequently underwent CT in the ED. However, Smith-Bindman et al¹⁶ concluded that it is acceptable for EPs to consider replacing CT with ultrasound as the initial imaging study in most patients. It should be noted that this study excluded certain high-risk populations, including solitary kidney and renal transplant patients. In addition, patients with a high body mass index were also excluded from the study due to the unreliability of ultrasound in obese patients.

 

  

 

Clinical Decision Score

Moore et al,¹⁷ authors of the Size, Topography, Location, Obstruction, Number of stones, and Evaluation (STONE) scoring system, developed a classification system for patients with suspected nephrolithiasis. This system places patients into low-, moderate-, and high-score groups, with corresponding probabilities of ureteral stone based on symptoms and epidemiological classifications.

The intent of the STONE system is to accurately predict, based on classification, the likelihood of a patient having a simple ureteral stone versus a more significant, complicated stone and to help guide which, if any, imaging studies are indicated. For example, a lower STONE score would help guide the decision to defer advanced imaging studies that would be unlikely to reveal an alternate serious diagnosis. Likewise, an individual with a high STONE score could potentially receive ultrasonography, reduced-dose CT, or no further imaging.

The STONE score performs fairly well and appears to be superior to physician gestalt, with an area under the receiver operating characteristic curve (AUC) of .78 compared to .68 with physician gestalt. This system, however, is not always accurate in its classification and has been shown to have 87% specificity at the high end to rule in stone and 96% sensitivity rate at the low end to rule out a stone. Of course, when using a clinical decision rule to rule in or rule out a stone, a tool with a very high specificity is preferred. Although the STONE scoring system does show promise, further studies are needed before it can be applied clinically.¹⁷

  

 

Treatment

Analgesia
By inhibiting prostaglandin synthesis, NSAIDs reduce inflammation and ureteral muscular hyperactivity.¹⁸ A recent Cochrane review of over 50 studies concluded that NSAIDs were effective in relieving acute renal colic pain.¹⁹ A systematic review by Holdgate and Pollock²⁰ shows that patients treated with NSAIDs achieve greater reductions in pain scores and are less likely to require additional analgesia in the short term compared to patients treated with opioids. Although opioid medications are effective in relieving pain associated with nephrolithiasis, this class of drugs can exacerbate the nausea often associated with this condition. This same study also showed that patients who were prescribed NSAIDs following an ED visit for renal colic required less medication for pain control, experienced less nausea, and had greater improvements in their pain.²⁰

Nevertheless, the utility of opiates as an adjunct therapy should not be overlooked. For example, in patients with renal colic, numerous studies show treatment with a combination of an NSAID and opiate provides superior pain relief compared to either treatment modality in isolation.²¹ Opioid analgesia may be indicated in patients in whom NSAIDs are not recommended or contraindicated (eg, elderly patients, patients with renal disease). While NSAIDs address the underlying pathophysiology associated with renal colic, they are sometimes not the best treatment option. Depending on the situation, treatment with an opioid should instead be considered.

Intravenous Fluid Therapy
A 2012 Cochrane Review of randomized control trials (RCT) on intravenous (IV) fluid therapy hydration/diuretic use concluded that there was “no reliable evidence in the literature to support the use of diuretics and high-volume fluid therapy for people with acute ureteric colic.” The review, however, did note that further investigation is warranted for a definitive answer.²² Another study by Springhart et al²³ showed no difference in pain or stone expulsion between large-volume (2 L IV fluids over 2 hours) and small-volume fluid administration (20 mL/h). Regarding administration, the use of IV fluids in renal colic is no different than the usual indications for fluid therapy in the ED and should be restricted to patients with signs of dehydration or kidney injury.

Many patients with renal colic will have decreased oral intake from the pain and nausea associated with the stone and may be vomiting. Under these circumstances, it is reasonable to rehydrate the patients, even though large-volume hydration with the intent of aiding stone expulsion or improving pain has not been shown efficacious. Conversely, in addition to the perceived benefit of rehydrating patients, a small amount of fluid hydration may improve the visualization of hydronephrosis on ultrasound.²⁴

Medical Expulsive Therapy
For many years, clinicians have considered the use of tamsulosin, an α1-receptor blocker, as well as nifedipine, a calcium channel blocker, in treating renal colic due to the theoretical benefit of reducing ureteral smooth muscle spasm/constriction thus expediting stone passage. Over the years, dozens of studies showed positive benefit in the use of medical expulsive therapy (MET). A 2014 Cochrane Review demonstrated that patients treated with α1-blockers experienced a higher stone-free rate and shorter time to stone expulsion, and concluded that α1-blockers should be offered as one of the primary treatment modalities in MET.²⁵ This review, however, has been criticized for using a number of studies with very small patient samples, non-peer-reviewed abstracts, and low-quality study designs.²⁶

 

More recently, in April 2015, Lancet published a large RCT from 24 hospitals in the United Kingdom, comparing placebo versus 400 mcg tamsulosin and 30 mg nifedipine. The authors concluded that “tamsulosin 400 mcg and nifedipine 30 mg are not effective at decreasing the need for further treatment to achieve stone clearance in 4 weeks for patients with expectantly managed ureteric colic.”²⁷ Another large double-blind, placebo-controlled, randomized, multicenter trial by Furyk et al²⁸ in July 2015 went a step further and evaluated distal stones, which have historically caused complications requiring intervention. They concluded that there was “no benefit overall of 0.4 mg of tamsulosin daily for patients with distal ureteric calculi less than or equal to 10 mm in terms of spontaneous passage, time to stone passage, pain, or analgesia requirements. In the subgroup with large stones (5 to 10 mm), tamsulosin did increase passage and should be considered.”²⁸ Based on these recent studies, the use of tamsulosin in patients with stones larger than 5 mm—but not those with smaller stones—appears to be an appropriate treatment option.

  

 

Patient Disposition

The American Urological Association cited indications for urgent/emergent urological interventions necessitating the need for inpatient admission and further workup.²⁹ Patients who do not fall into any of the categories outlined in the Table may be seen on an outpatient basis. These patients may be treated symptomatically until they can follow up with a urologist, who will determine expectant management versus intervention.

In many communities, initial follow-up with a primary care physician (PCP), rather than a urologist, is standard for patients who are likely to pass the stone spontaneously—specifically those with nonobstructing stones <5 mm in diameter and no history of prior complicated kidney stone. Any patient discharged home with a suspected or confirmed diagnosis of nephrolithiasis should be instructed to return to the ED if he or she is unable to take the prescribed medications due to excessive nausea/vomiting; becomes febrile;  develops severe pain despite oral medication; or develops any other worrisome symptoms. All of these indicate that he or she may have progressed to complicated nephrolithiasis requiring further workup and potential intervention (Table). Computed tomography should be pursued in a patient whose stone is symptomatic enough to warrant inpatient admission. For example, a patient who is febrile or whose urinalysis is suggestive of infection—in addition to a high clinical suspicion of renal colic—should undergo CT evaluation to rule out an obstructing infected stone or another possible diagnosis. Computed tomography investigation is required in any patient who presents with colicky pain or flank pain and whose condition is considered complicated.

  

 

Prognosis

The majority of stones <5mm will pass spontaneously.³⁰ Larger stones may still pass spontaneously but are more likely to require lithotripsy or other urologic intervention; therefore, patients with stones >5 mm should be referred to urology services.³⁰

Recurrence
Patients with a first-time kidney stone have a 30% to 50% chance of disease recurrence within 5 years,³¹ and a 60% to 80% chance of recurrence during their lifetime.³² Those with a family history of nephrolithiasis are likely to develop an earlier onset of stones as well as experience more frequent recurrent episodes.³³ Patients with recurrent disease should undergo outpatient risk stratification, including stone-composition analysis and assessment for modifiable risk factors.

  

 

Case Conclusion

The patient’s urinalysis demonstrated microscopic hematuria; blood urea nitrogen and creatinine levels were within normal limits. As the patient was tachycardic and appeared mildly dehydrated, an IV infusion of 1 L normal saline was initiated, along with ketorolac and ondansetron for symptomatic relief. A POC ultrasound of the right kidney revealed mild-to-moderate hydronephrosis; the left kidney appeared sonographically normal. Since this patient had no history of nephrolithiasis, a nonenhanced CT of the abdomen was obtained, which revealed moderate, right-sided hydronephrosis and a 3-mm distal ureteral stone. Once the patient’s symptoms were controlled, she was discharged home with a prescription for ibuprofen for symptomatic relief and instructions to follow up with her PCP.

  

 

Conclusion

The evaluation and treatment of nephrolithiasis is important due to its increasing prevalence, as well as implications on costs to the health-care system and to patients themselves. The workup and treatment of nephrolithiasis has been and continues to be the subject of much controversy. Until very recently, treatment recommendations were founded on physiological theories more so than robust research. In an era where improved imaging technology is becoming more readily available in the ED, EPs should weigh the pros and cons of its utilization for common ED complaints such as nephrolithiasis.

 

  

 

---

Dr Parsa is an assistant professor in the department of emergency medicine, Texas Tech University Health Sciences Center, El Paso. Dr Khafi is a resident in the department of emergency medicine, Texas Tech University Health Sciences Center, El Paso.

 

Case

A 39-year-old woman presented to the ED with a chief complaint of intermittent right flank pain that radiated into her groin area. She stated the pain had begun suddenly, 4 hours prior to arrival, and was accompanied by nausea and vomiting. The patient said that she had taken acetaminophen for the pain, but had received no relief. Regarding history, according to the patient, her last menstrual period ended 2 days earlier. She denied any urinary symptoms, diarrhea, or constipation. She had no history of abdominal surgery and was currently not on any medications.

The patient’s vital signs at presentation were: temperature 98.7°F; blood pressure, 130/90 mm Hg; heart rate, 110 beats/minute; and respiratory rate, 18 breaths/minute. Oxygen saturation was 98% on room air. On physical examination, she appeared to be in mild distress, pacing around the room. There was moderate right costovertebral tenderness on percussion; the abdomen was soft and nontender.

  

 

Incidence

As ED visits for nephrolithiasis are increasing, so too are the health-care costs associated with this condition. Between 1992 and 2009, emergent-care presentations for nephrolithiasis rose from 178 to 340 visits per 100,000 individuals.¹ Approximately 1 in 11 people in the United States will be affected by nephrolithiasis during their lifetime.² Estimated health-care costs associated with these complaints were roughly $2 billion in 2000—an increase of 50% since 1994.²

  

 

Evaluation and Diagnosis

Laboratory Evaluation
Urinalysis is one of the initial studies for patients with suspected nephrolithiasis. Although hematuria is a classic finding associated with renal calculi, its sensitivity on microscopic analysis is around 84%. Therefore, the absence of hematuria does not exclude renal colic in the differential diagnosis.³

In addition to detecting hematuria, urinalysis can also reveal an underlying infection. One study by Abrahamian et al⁴ found that roughly 8% of patients presenting with acute nephrolithiasis had a urinary tract infection (UTI)—many without any clinical findings of infection. The presence of pyuria, however, has only moderate accuracy in identifying UTIs in patients with kidney stones.⁴ If an infected stone cannot be excluded clinically, computed tomography (CT) is indicated.

Mild leukocytosis (ie, <15,000 cells/mcL) is another common finding in patients with acute renal colic.⁵ A leukocyte count >15,000 cells/mcL is suspicious for infection or other pathology. A blood-chemistry panel to evaluate renal function is appropriate as a baseline—particularly for patients in whom treatment with a nonsteroidal anti-inflammatory (NSAID) drug is anticipated.

Unenhanced Computed Tomography
With the ability to visualize renal calculi (Figure 1), the use of noncontrast CT has become a standard initial imaging modality in assessing patients with renal colic. Between 1992 and 2009, the use of CT to evaluate patients presenting with flank pain for suspected renal colic more than tripled from 21% to 71%.⁶ An analysis performed by the American College of National Radiology Data Registry⁷ shows the mean radiation dose given by institutions for renal colic CT is unnecessarily high, and that few institutions follow CT-stone protocols aimed at minimizing radiation exposure while still maintaining proper diagnostic accuracy. A typical CT of the abdomen and pelvis is equivalent to over 100 two-view chest X-rays.⁸ Though controversial, data from a white paper by the American College of Radiology suggest that the ionizing radiation exposure from just one CT for renal colic causes an increase in lifetime cancer risk.⁹

Despite the increase in CT imaging to evaluate patients presenting to the ED with nephrolithiasis/flank pain, the proportion of patients diagnosed with a kidney stone remained the same between 2000 and 2008, with no significant change in outcomes.^10-12 Moreover, the use of CT as an initial imaging modality in patients presenting with flank pain—but with no sign of infection—is unlikely to reveal important alternative findings.¹³

Regarding the sensitivity of CT in detecting nephrolithiasis, one study demonstrates a sensitivity of 100% and a specificity of 94% for noncontrast CT.¹⁴ Controversy, however, still exists regarding the necessity and utility of CT in diagnosing nephrolithiasis,¹⁵ and CT is one of the top 10 tests included in the American College of Emergency Physicians (ACEP) 2014 Choosing Wisely campaign. In this campaign, ACEP recommended emergency physicians (EPs) avoid abdominal and pelvic CT in otherwise healthy patients younger than age 50 years who present with symptoms consistent with uncomplicated renal colic and who have a known history of nephrolithiasis or ureterolithiasis.¹⁵ The ACEP also noted that CTs in this context do not often change treatment decisions and are associated with unnecessary radiation exposure and cost.¹⁵

While keeping the aforementioned recommendations in mind, if an EP intends to refer a renal colic patient to a urologist a CT scan is necessary either in the ED or as an outpatient. In all cases (except perhaps in patients in whom there is a history of renal stones), the urologist will need this study to determine the size and location of the stone in order to provide recommendations for management.

Ultrasound

Ultrasound is another imaging modality with a high sensitivity in detecting renal calculi (Figure 2), and its role in the diagnosis of nephrolithiasis continues to evolve. A study by Smith-Bindman et al¹⁶ showed that in ED patients with symptoms suggestive of kidney stones, ultrasound as the initial imaging study was associated with lower cumulative radiation exposure than CT alone, with no significant differences in high-risk diagnosis with complications, serious adverse events, pain scores, return ED visits, or hospitalizations. In this study, 40% of patients who received point-of-care (POC) ultrasound and 27% who received radiology ultrasound subsequently underwent CT in the ED. However, Smith-Bindman et al¹⁶ concluded that it is acceptable for EPs to consider replacing CT with ultrasound as the initial imaging study in most patients. It should be noted that this study excluded certain high-risk populations, including solitary kidney and renal transplant patients. In addition, patients with a high body mass index were also excluded from the study due to the unreliability of ultrasound in obese patients.

 

  

 

Clinical Decision Score

Moore et al,¹⁷ authors of the Size, Topography, Location, Obstruction, Number of stones, and Evaluation (STONE) scoring system, developed a classification system for patients with suspected nephrolithiasis. This system places patients into low-, moderate-, and high-score groups, with corresponding probabilities of ureteral stone based on symptoms and epidemiological classifications.

The intent of the STONE system is to accurately predict, based on classification, the likelihood of a patient having a simple ureteral stone versus a more significant, complicated stone and to help guide which, if any, imaging studies are indicated. For example, a lower STONE score would help guide the decision to defer advanced imaging studies that would be unlikely to reveal an alternate serious diagnosis. Likewise, an individual with a high STONE score could potentially receive ultrasonography, reduced-dose CT, or no further imaging.

The STONE score performs fairly well and appears to be superior to physician gestalt, with an area under the receiver operating characteristic curve (AUC) of .78 compared to .68 with physician gestalt. This system, however, is not always accurate in its classification and has been shown to have 87% specificity at the high end to rule in stone and 96% sensitivity rate at the low end to rule out a stone. Of course, when using a clinical decision rule to rule in or rule out a stone, a tool with a very high specificity is preferred. Although the STONE scoring system does show promise, further studies are needed before it can be applied clinically.¹⁷

  

 

Treatment

Analgesia
By inhibiting prostaglandin synthesis, NSAIDs reduce inflammation and ureteral muscular hyperactivity.¹⁸ A recent Cochrane review of over 50 studies concluded that NSAIDs were effective in relieving acute renal colic pain.¹⁹ A systematic review by Holdgate and Pollock²⁰ shows that patients treated with NSAIDs achieve greater reductions in pain scores and are less likely to require additional analgesia in the short term compared to patients treated with opioids. Although opioid medications are effective in relieving pain associated with nephrolithiasis, this class of drugs can exacerbate the nausea often associated with this condition. This same study also showed that patients who were prescribed NSAIDs following an ED visit for renal colic required less medication for pain control, experienced less nausea, and had greater improvements in their pain.²⁰

Nevertheless, the utility of opiates as an adjunct therapy should not be overlooked. For example, in patients with renal colic, numerous studies show treatment with a combination of an NSAID and opiate provides superior pain relief compared to either treatment modality in isolation.²¹ Opioid analgesia may be indicated in patients in whom NSAIDs are not recommended or contraindicated (eg, elderly patients, patients with renal disease). While NSAIDs address the underlying pathophysiology associated with renal colic, they are sometimes not the best treatment option. Depending on the situation, treatment with an opioid should instead be considered.

Intravenous Fluid Therapy
A 2012 Cochrane Review of randomized control trials (RCT) on intravenous (IV) fluid therapy hydration/diuretic use concluded that there was “no reliable evidence in the literature to support the use of diuretics and high-volume fluid therapy for people with acute ureteric colic.” The review, however, did note that further investigation is warranted for a definitive answer.²² Another study by Springhart et al²³ showed no difference in pain or stone expulsion between large-volume (2 L IV fluids over 2 hours) and small-volume fluid administration (20 mL/h). Regarding administration, the use of IV fluids in renal colic is no different than the usual indications for fluid therapy in the ED and should be restricted to patients with signs of dehydration or kidney injury.

Many patients with renal colic will have decreased oral intake from the pain and nausea associated with the stone and may be vomiting. Under these circumstances, it is reasonable to rehydrate the patients, even though large-volume hydration with the intent of aiding stone expulsion or improving pain has not been shown efficacious. Conversely, in addition to the perceived benefit of rehydrating patients, a small amount of fluid hydration may improve the visualization of hydronephrosis on ultrasound.²⁴

Medical Expulsive Therapy
For many years, clinicians have considered the use of tamsulosin, an α1-receptor blocker, as well as nifedipine, a calcium channel blocker, in treating renal colic due to the theoretical benefit of reducing ureteral smooth muscle spasm/constriction thus expediting stone passage. Over the years, dozens of studies showed positive benefit in the use of medical expulsive therapy (MET). A 2014 Cochrane Review demonstrated that patients treated with α1-blockers experienced a higher stone-free rate and shorter time to stone expulsion, and concluded that α1-blockers should be offered as one of the primary treatment modalities in MET.²⁵ This review, however, has been criticized for using a number of studies with very small patient samples, non-peer-reviewed abstracts, and low-quality study designs.²⁶

 

More recently, in April 2015, Lancet published a large RCT from 24 hospitals in the United Kingdom, comparing placebo versus 400 mcg tamsulosin and 30 mg nifedipine. The authors concluded that “tamsulosin 400 mcg and nifedipine 30 mg are not effective at decreasing the need for further treatment to achieve stone clearance in 4 weeks for patients with expectantly managed ureteric colic.”²⁷ Another large double-blind, placebo-controlled, randomized, multicenter trial by Furyk et al²⁸ in July 2015 went a step further and evaluated distal stones, which have historically caused complications requiring intervention. They concluded that there was “no benefit overall of 0.4 mg of tamsulosin daily for patients with distal ureteric calculi less than or equal to 10 mm in terms of spontaneous passage, time to stone passage, pain, or analgesia requirements. In the subgroup with large stones (5 to 10 mm), tamsulosin did increase passage and should be considered.”²⁸ Based on these recent studies, the use of tamsulosin in patients with stones larger than 5 mm—but not those with smaller stones—appears to be an appropriate treatment option.

  

 

Patient Disposition

The American Urological Association cited indications for urgent/emergent urological interventions necessitating the need for inpatient admission and further workup.²⁹ Patients who do not fall into any of the categories outlined in the Table may be seen on an outpatient basis. These patients may be treated symptomatically until they can follow up with a urologist, who will determine expectant management versus intervention.

In many communities, initial follow-up with a primary care physician (PCP), rather than a urologist, is standard for patients who are likely to pass the stone spontaneously—specifically those with nonobstructing stones <5 mm in diameter and no history of prior complicated kidney stone. Any patient discharged home with a suspected or confirmed diagnosis of nephrolithiasis should be instructed to return to the ED if he or she is unable to take the prescribed medications due to excessive nausea/vomiting; becomes febrile;  develops severe pain despite oral medication; or develops any other worrisome symptoms. All of these indicate that he or she may have progressed to complicated nephrolithiasis requiring further workup and potential intervention (Table). Computed tomography should be pursued in a patient whose stone is symptomatic enough to warrant inpatient admission. For example, a patient who is febrile or whose urinalysis is suggestive of infection—in addition to a high clinical suspicion of renal colic—should undergo CT evaluation to rule out an obstructing infected stone or another possible diagnosis. Computed tomography investigation is required in any patient who presents with colicky pain or flank pain and whose condition is considered complicated.

  

 

Prognosis

The majority of stones <5mm will pass spontaneously.³⁰ Larger stones may still pass spontaneously but are more likely to require lithotripsy or other urologic intervention; therefore, patients with stones >5 mm should be referred to urology services.³⁰

Recurrence
Patients with a first-time kidney stone have a 30% to 50% chance of disease recurrence within 5 years,³¹ and a 60% to 80% chance of recurrence during their lifetime.³² Those with a family history of nephrolithiasis are likely to develop an earlier onset of stones as well as experience more frequent recurrent episodes.³³ Patients with recurrent disease should undergo outpatient risk stratification, including stone-composition analysis and assessment for modifiable risk factors.

  

 

Case Conclusion

The patient’s urinalysis demonstrated microscopic hematuria; blood urea nitrogen and creatinine levels were within normal limits. As the patient was tachycardic and appeared mildly dehydrated, an IV infusion of 1 L normal saline was initiated, along with ketorolac and ondansetron for symptomatic relief. A POC ultrasound of the right kidney revealed mild-to-moderate hydronephrosis; the left kidney appeared sonographically normal. Since this patient had no history of nephrolithiasis, a nonenhanced CT of the abdomen was obtained, which revealed moderate, right-sided hydronephrosis and a 3-mm distal ureteral stone. Once the patient’s symptoms were controlled, she was discharged home with a prescription for ibuprofen for symptomatic relief and instructions to follow up with her PCP.

  

 

Conclusion

The evaluation and treatment of nephrolithiasis is important due to its increasing prevalence, as well as implications on costs to the health-care system and to patients themselves. The workup and treatment of nephrolithiasis has been and continues to be the subject of much controversy. Until very recently, treatment recommendations were founded on physiological theories more so than robust research. In an era where improved imaging technology is becoming more readily available in the ED, EPs should weigh the pros and cons of its utilization for common ED complaints such as nephrolithiasis.

 

  

 

---

Dr Parsa is an assistant professor in the department of emergency medicine, Texas Tech University Health Sciences Center, El Paso. Dr Khafi is a resident in the department of emergency medicine, Texas Tech University Health Sciences Center, El Paso.

 

Case

A 39-year-old woman presented to the ED with a chief complaint of intermittent right flank pain that radiated into her groin area. She stated the pain had begun suddenly, 4 hours prior to arrival, and was accompanied by nausea and vomiting. The patient said that she had taken acetaminophen for the pain, but had received no relief. Regarding history, according to the patient, her last menstrual period ended 2 days earlier. She denied any urinary symptoms, diarrhea, or constipation. She had no history of abdominal surgery and was currently not on any medications.

The patient’s vital signs at presentation were: temperature 98.7°F; blood pressure, 130/90 mm Hg; heart rate, 110 beats/minute; and respiratory rate, 18 breaths/minute. Oxygen saturation was 98% on room air. On physical examination, she appeared to be in mild distress, pacing around the room. There was moderate right costovertebral tenderness on percussion; the abdomen was soft and nontender.

  

 

Incidence

As ED visits for nephrolithiasis are increasing, so too are the health-care costs associated with this condition. Between 1992 and 2009, emergent-care presentations for nephrolithiasis rose from 178 to 340 visits per 100,000 individuals.¹ Approximately 1 in 11 people in the United States will be affected by nephrolithiasis during their lifetime.² Estimated health-care costs associated with these complaints were roughly $2 billion in 2000—an increase of 50% since 1994.²

  

 

Evaluation and Diagnosis

Laboratory Evaluation
Urinalysis is one of the initial studies for patients with suspected nephrolithiasis. Although hematuria is a classic finding associated with renal calculi, its sensitivity on microscopic analysis is around 84%. Therefore, the absence of hematuria does not exclude renal colic in the differential diagnosis.³

In addition to detecting hematuria, urinalysis can also reveal an underlying infection. One study by Abrahamian et al⁴ found that roughly 8% of patients presenting with acute nephrolithiasis had a urinary tract infection (UTI)—many without any clinical findings of infection. The presence of pyuria, however, has only moderate accuracy in identifying UTIs in patients with kidney stones.⁴ If an infected stone cannot be excluded clinically, computed tomography (CT) is indicated.

Mild leukocytosis (ie, <15,000 cells/mcL) is another common finding in patients with acute renal colic.⁵ A leukocyte count >15,000 cells/mcL is suspicious for infection or other pathology. A blood-chemistry panel to evaluate renal function is appropriate as a baseline—particularly for patients in whom treatment with a nonsteroidal anti-inflammatory (NSAID) drug is anticipated.

Unenhanced Computed Tomography
With the ability to visualize renal calculi (Figure 1), the use of noncontrast CT has become a standard initial imaging modality in assessing patients with renal colic. Between 1992 and 2009, the use of CT to evaluate patients presenting with flank pain for suspected renal colic more than tripled from 21% to 71%.⁶ An analysis performed by the American College of National Radiology Data Registry⁷ shows the mean radiation dose given by institutions for renal colic CT is unnecessarily high, and that few institutions follow CT-stone protocols aimed at minimizing radiation exposure while still maintaining proper diagnostic accuracy. A typical CT of the abdomen and pelvis is equivalent to over 100 two-view chest X-rays.⁸ Though controversial, data from a white paper by the American College of Radiology suggest that the ionizing radiation exposure from just one CT for renal colic causes an increase in lifetime cancer risk.⁹

Despite the increase in CT imaging to evaluate patients presenting to the ED with nephrolithiasis/flank pain, the proportion of patients diagnosed with a kidney stone remained the same between 2000 and 2008, with no significant change in outcomes.^10-12 Moreover, the use of CT as an initial imaging modality in patients presenting with flank pain—but with no sign of infection—is unlikely to reveal important alternative findings.¹³

Regarding the sensitivity of CT in detecting nephrolithiasis, one study demonstrates a sensitivity of 100% and a specificity of 94% for noncontrast CT.¹⁴ Controversy, however, still exists regarding the necessity and utility of CT in diagnosing nephrolithiasis,¹⁵ and CT is one of the top 10 tests included in the American College of Emergency Physicians (ACEP) 2014 Choosing Wisely campaign. In this campaign, ACEP recommended emergency physicians (EPs) avoid abdominal and pelvic CT in otherwise healthy patients younger than age 50 years who present with symptoms consistent with uncomplicated renal colic and who have a known history of nephrolithiasis or ureterolithiasis.¹⁵ The ACEP also noted that CTs in this context do not often change treatment decisions and are associated with unnecessary radiation exposure and cost.¹⁵

While keeping the aforementioned recommendations in mind, if an EP intends to refer a renal colic patient to a urologist a CT scan is necessary either in the ED or as an outpatient. In all cases (except perhaps in patients in whom there is a history of renal stones), the urologist will need this study to determine the size and location of the stone in order to provide recommendations for management.

Ultrasound

Ultrasound is another imaging modality with a high sensitivity in detecting renal calculi (Figure 2), and its role in the diagnosis of nephrolithiasis continues to evolve. A study by Smith-Bindman et al¹⁶ showed that in ED patients with symptoms suggestive of kidney stones, ultrasound as the initial imaging study was associated with lower cumulative radiation exposure than CT alone, with no significant differences in high-risk diagnosis with complications, serious adverse events, pain scores, return ED visits, or hospitalizations. In this study, 40% of patients who received point-of-care (POC) ultrasound and 27% who received radiology ultrasound subsequently underwent CT in the ED. However, Smith-Bindman et al¹⁶ concluded that it is acceptable for EPs to consider replacing CT with ultrasound as the initial imaging study in most patients. It should be noted that this study excluded certain high-risk populations, including solitary kidney and renal transplant patients. In addition, patients with a high body mass index were also excluded from the study due to the unreliability of ultrasound in obese patients.

 

  

 

Clinical Decision Score

Moore et al,¹⁷ authors of the Size, Topography, Location, Obstruction, Number of stones, and Evaluation (STONE) scoring system, developed a classification system for patients with suspected nephrolithiasis. This system places patients into low-, moderate-, and high-score groups, with corresponding probabilities of ureteral stone based on symptoms and epidemiological classifications.

The intent of the STONE system is to accurately predict, based on classification, the likelihood of a patient having a simple ureteral stone versus a more significant, complicated stone and to help guide which, if any, imaging studies are indicated. For example, a lower STONE score would help guide the decision to defer advanced imaging studies that would be unlikely to reveal an alternate serious diagnosis. Likewise, an individual with a high STONE score could potentially receive ultrasonography, reduced-dose CT, or no further imaging.

The STONE score performs fairly well and appears to be superior to physician gestalt, with an area under the receiver operating characteristic curve (AUC) of .78 compared to .68 with physician gestalt. This system, however, is not always accurate in its classification and has been shown to have 87% specificity at the high end to rule in stone and 96% sensitivity rate at the low end to rule out a stone. Of course, when using a clinical decision rule to rule in or rule out a stone, a tool with a very high specificity is preferred. Although the STONE scoring system does show promise, further studies are needed before it can be applied clinically.¹⁷

  

 

Treatment

Analgesia
By inhibiting prostaglandin synthesis, NSAIDs reduce inflammation and ureteral muscular hyperactivity.¹⁸ A recent Cochrane review of over 50 studies concluded that NSAIDs were effective in relieving acute renal colic pain.¹⁹ A systematic review by Holdgate and Pollock²⁰ shows that patients treated with NSAIDs achieve greater reductions in pain scores and are less likely to require additional analgesia in the short term compared to patients treated with opioids. Although opioid medications are effective in relieving pain associated with nephrolithiasis, this class of drugs can exacerbate the nausea often associated with this condition. This same study also showed that patients who were prescribed NSAIDs following an ED visit for renal colic required less medication for pain control, experienced less nausea, and had greater improvements in their pain.²⁰

Nevertheless, the utility of opiates as an adjunct therapy should not be overlooked. For example, in patients with renal colic, numerous studies show treatment with a combination of an NSAID and opiate provides superior pain relief compared to either treatment modality in isolation.²¹ Opioid analgesia may be indicated in patients in whom NSAIDs are not recommended or contraindicated (eg, elderly patients, patients with renal disease). While NSAIDs address the underlying pathophysiology associated with renal colic, they are sometimes not the best treatment option. Depending on the situation, treatment with an opioid should instead be considered.

Intravenous Fluid Therapy
A 2012 Cochrane Review of randomized control trials (RCT) on intravenous (IV) fluid therapy hydration/diuretic use concluded that there was “no reliable evidence in the literature to support the use of diuretics and high-volume fluid therapy for people with acute ureteric colic.” The review, however, did note that further investigation is warranted for a definitive answer.²² Another study by Springhart et al²³ showed no difference in pain or stone expulsion between large-volume (2 L IV fluids over 2 hours) and small-volume fluid administration (20 mL/h). Regarding administration, the use of IV fluids in renal colic is no different than the usual indications for fluid therapy in the ED and should be restricted to patients with signs of dehydration or kidney injury.

Many patients with renal colic will have decreased oral intake from the pain and nausea associated with the stone and may be vomiting. Under these circumstances, it is reasonable to rehydrate the patients, even though large-volume hydration with the intent of aiding stone expulsion or improving pain has not been shown efficacious. Conversely, in addition to the perceived benefit of rehydrating patients, a small amount of fluid hydration may improve the visualization of hydronephrosis on ultrasound.²⁴

Medical Expulsive Therapy
For many years, clinicians have considered the use of tamsulosin, an α1-receptor blocker, as well as nifedipine, a calcium channel blocker, in treating renal colic due to the theoretical benefit of reducing ureteral smooth muscle spasm/constriction thus expediting stone passage. Over the years, dozens of studies showed positive benefit in the use of medical expulsive therapy (MET). A 2014 Cochrane Review demonstrated that patients treated with α1-blockers experienced a higher stone-free rate and shorter time to stone expulsion, and concluded that α1-blockers should be offered as one of the primary treatment modalities in MET.²⁵ This review, however, has been criticized for using a number of studies with very small patient samples, non-peer-reviewed abstracts, and low-quality study designs.²⁶

 

More recently, in April 2015, Lancet published a large RCT from 24 hospitals in the United Kingdom, comparing placebo versus 400 mcg tamsulosin and 30 mg nifedipine. The authors concluded that “tamsulosin 400 mcg and nifedipine 30 mg are not effective at decreasing the need for further treatment to achieve stone clearance in 4 weeks for patients with expectantly managed ureteric colic.”²⁷ Another large double-blind, placebo-controlled, randomized, multicenter trial by Furyk et al²⁸ in July 2015 went a step further and evaluated distal stones, which have historically caused complications requiring intervention. They concluded that there was “no benefit overall of 0.4 mg of tamsulosin daily for patients with distal ureteric calculi less than or equal to 10 mm in terms of spontaneous passage, time to stone passage, pain, or analgesia requirements. In the subgroup with large stones (5 to 10 mm), tamsulosin did increase passage and should be considered.”²⁸ Based on these recent studies, the use of tamsulosin in patients with stones larger than 5 mm—but not those with smaller stones—appears to be an appropriate treatment option.

  

 

Patient Disposition

The American Urological Association cited indications for urgent/emergent urological interventions necessitating the need for inpatient admission and further workup.²⁹ Patients who do not fall into any of the categories outlined in the Table may be seen on an outpatient basis. These patients may be treated symptomatically until they can follow up with a urologist, who will determine expectant management versus intervention.

In many communities, initial follow-up with a primary care physician (PCP), rather than a urologist, is standard for patients who are likely to pass the stone spontaneously—specifically those with nonobstructing stones <5 mm in diameter and no history of prior complicated kidney stone. Any patient discharged home with a suspected or confirmed diagnosis of nephrolithiasis should be instructed to return to the ED if he or she is unable to take the prescribed medications due to excessive nausea/vomiting; becomes febrile;  develops severe pain despite oral medication; or develops any other worrisome symptoms. All of these indicate that he or she may have progressed to complicated nephrolithiasis requiring further workup and potential intervention (Table). Computed tomography should be pursued in a patient whose stone is symptomatic enough to warrant inpatient admission. For example, a patient who is febrile or whose urinalysis is suggestive of infection—in addition to a high clinical suspicion of renal colic—should undergo CT evaluation to rule out an obstructing infected stone or another possible diagnosis. Computed tomography investigation is required in any patient who presents with colicky pain or flank pain and whose condition is considered complicated.

  

 

Prognosis

The majority of stones <5mm will pass spontaneously.³⁰ Larger stones may still pass spontaneously but are more likely to require lithotripsy or other urologic intervention; therefore, patients with stones >5 mm should be referred to urology services.³⁰

Recurrence
Patients with a first-time kidney stone have a 30% to 50% chance of disease recurrence within 5 years,³¹ and a 60% to 80% chance of recurrence during their lifetime.³² Those with a family history of nephrolithiasis are likely to develop an earlier onset of stones as well as experience more frequent recurrent episodes.³³ Patients with recurrent disease should undergo outpatient risk stratification, including stone-composition analysis and assessment for modifiable risk factors.

  

 

Case Conclusion

The patient’s urinalysis demonstrated microscopic hematuria; blood urea nitrogen and creatinine levels were within normal limits. As the patient was tachycardic and appeared mildly dehydrated, an IV infusion of 1 L normal saline was initiated, along with ketorolac and ondansetron for symptomatic relief. A POC ultrasound of the right kidney revealed mild-to-moderate hydronephrosis; the left kidney appeared sonographically normal. Since this patient had no history of nephrolithiasis, a nonenhanced CT of the abdomen was obtained, which revealed moderate, right-sided hydronephrosis and a 3-mm distal ureteral stone. Once the patient’s symptoms were controlled, she was discharged home with a prescription for ibuprofen for symptomatic relief and instructions to follow up with her PCP.

  

 

Conclusion

The evaluation and treatment of nephrolithiasis is important due to its increasing prevalence, as well as implications on costs to the health-care system and to patients themselves. The workup and treatment of nephrolithiasis has been and continues to be the subject of much controversy. Until very recently, treatment recommendations were founded on physiological theories more so than robust research. In an era where improved imaging technology is becoming more readily available in the ED, EPs should weigh the pros and cons of its utilization for common ED complaints such as nephrolithiasis.

 

  

 

---

Dr Parsa is an assistant professor in the department of emergency medicine, Texas Tech University Health Sciences Center, El Paso. Dr Khafi is a resident in the department of emergency medicine, Texas Tech University Health Sciences Center, El Paso.

The beach-chair position (BCP) is commonly used for both arthroscopic and open shoulder surgery. This technique positions the shoulder in an anatomical upright position, facilitating shoulder access and visualization.¹ Compared with the lateral decubitus position, the BCP also improves airway access, reduces bleeding, and lessens the risk for brachial plexus injury.²

Despite the advantages of using the BCP, there have been multiple reports of catastrophic neurologic complications, including severe brain damage and death, in relatively healthy patients without any known risk factors.^3-6 The definitive etiology of these complications remains unclear, but it has been hypothesized that BCP use may be an independent risk factor for cerebrovascular ischemia,^1,5-16 as the upright position can cause hypotension leading to increased risk for cerebral hypoperfusion.^7-11,17 Reducing cerebral perfusion pressure below critical thresholds may result in permanent neurologic injury.^4-6,14 Therefore, monitoring of cerebral perfusion and optimization of intraoperative cerebral oxygenation have been recommended to help avoid potential neurologic complications. However, a direct relationship between intraoperative cerebral desaturation events (CDEs) and postoperative neurocognitive deficits has not been definitively established.^1,9-12

To put into perspective the importance of detecting and preventing CDEs and neurologic complications, we can consider the incidence of fatal pulmonary embolism associated with total joint arthroplasty. Although the incidence is very low, about 0.1% to 2.0%, some form of venous thromboembolism prophylaxis is the standard of care for helping prevent this serious complication. Similarly, catastrophic neurologic complications of upright shoulder arthroscopy are very rare, but it is still important to consider measures that help minimize them.

We reviewed the literature for the incidence of postoperative neurocognitive deficits, number of reported neurocognitive complications, and incidence of intraoperative CDEs in patients who underwent arthroscopic shoulder surgery in the BCP.

Methods

Dr. Salazar and Dr. Hazel independently searched the Medline, Cochrane, and Embase databases for case series, prospective studies, and cohort studies that reported neurocognitive complications associated with the BCP and the incidence of intraoperative CDEs. The authors used beach chair, desaturation, near infrared spectroscopy, and shoulder as medical subject headings (MeSH). In addition, bibliographies of retrieved articles were checked for studies that the search terms may have missed. Eighty-one publications were identified and reviewed for possible inclusion.

Next, the same 2 authors reviewed the titles and abstracts for relevance and determined which articles had potential to contribute to the study. Only English-language publications were considered for inclusion. To review the incidence of postoperative neurocognitive deficits, we included only those studies with more than 25 patients, documentation of postoperative complications, and arthroscopic shoulder surgery performed with the patient in the seated, semi-upright, or BCP. Only studies with at least 25 patients were used in order to increase the power and improve the level of evidence. To review reported cases of neurocognitive complications, we included all relevant case reports and case series. To review the incidence of intraoperative CDEs and investigate their relationship with postoperative neurocognitive deficits, we included studies that reported on use of intraoperative cerebral perfusion monitoring. Modalities used in these studies included near infrared spectroscopy, electroencephalography, and invasive blood pressure monitoring calculated at the brain level. Studies were excluded if they did not involve arthroscopic shoulder surgery or were not conducted with human subjects.

Information recorded for each study included general information such as author and publication year, type of study, number of patients enrolled, type of intraoperative monitoring, anesthesia protocol, number of patients with CDEs, and number of patients with neurocognitive complications after surgery.

Results

Our search identified 81 publications for potential inclusion. Our first aim was to identify the overall incidence of reported neurocognitive deficits after arthroscopic shoulder surgery with the patient in the BCP. We identified 10 studies (Table 1) that met the inclusion criteria. Among the 24,701 patients in these 10 studies, there was only 1 reported case of neurocognitive deficit after surgery, in a mixed prospective-retrospective study of 15,014 cases by Rohrbaugh and colleagues.18 The deficit they reported was an ischemic cerebral vascular accident. The 0.0067% incidence in their study demonstrates how rare the complication is. Two large retrospective studies (Ns = 4169 and 5177 patients) found no postoperative neurocognitive complications.^19,20 Only 3 studies performed formal postoperative cognitive testing. Salazar and colleagues²¹ used the Repeatable Battery for the Assessment of Neuropsychological Status before and after surgery, and Gillespie and colleagues⁸ and Lee and colleagues¹⁰ used the Mini–Mental State Examination before and after surgery. Total incidence of reported neurocognitive deficits from our review was 0.004% (1/24,701).

Our second aim was to review all reported cases of neurocognitive complications after arthroscopic shoulder surgery with the patient in the BCP. We identified 4 publications that fit our inclusion criteria (Table 2). Pohl and Cullen6 described 4 cases of ischemic brain injury after arthroscopic shoulder surgery with the patient in the BCP. Age range was 47 to 57 years. Specific intraoperative cerebral monitoring was not used. However, these patients had several episodes of intraoperative hypotension (systolic blood pressures, 80-90 mm Hg), measured with a traditional blood pressure cuff on the arm. In general, these patients had minimal cerebrovascular risk factors and no known preexisting cerebrovascular disease. Drummond and colleagues²² described an ischemic stroke in a 50-year-old man after arthroscopic subacromial decompression and open rotator cuff repair that resulted in unresolved right hemiplegia. Subsequent diagnostic investigation revealed an asymmetry of the circle of Willis resulting in limited flow to the left anterior and middle cerebral artery distributions. Bhatti and Enneking³ reported the case of a 64-year-old man who lost vision in the right eye immediately after arthroscopic rotator cuff repair. His vision improved spontaneously the next morning and continued to improve over the next 6 months—he regained 20/20 vision with some residual optic neuropathy.

 

Our third aim was to determine the incidence of intraoperative CDEs during arthroscopic shoulder surgery with the patient in the BCP. Incidence of CDEs varied widely among the 7 studies reviewed (Table 3). Minimum incidence of intraoperative CDE was 0% in a cohort of 30 patients,¹ and maximum incidence was 80% in a study of 61 patients,¹² all of whom underwent elective arthroscopic shoulder surgery in the BCP. Although there was wide variability in CDE incidence, the studies were consistent with respect to their definition of a CDE. Most authors used a decrease in regional cerebral tissue oxygen saturation of 20% or more from baseline, or an absolute value up to 55%, to define a CDE. None of the 7 studies reviewed reported a clinically significant adverse neurocognitive event.

Discussion

Of concern, there have been several surveys, case reports, and small case series of previously healthy patients who had no known risk factors, underwent arthroscopic shoulder surgery in the BCP, and developed unanticipated postoperative neurologic complications.^4-6,14 Beach-chair positioning during surgical procedures has been implicated as a contributing factor leading to cerebral hypoperfusion with potential for cerebral ischemia.^1,12,23 These changes in cerebral perfusion pressure are thought to be the major determinant of poor neurologic outcomes. Such reports have exposed the potential need for heightened vigilance, alternative anesthesia techniques, and improved monitoring, though the exact etiology of the central nervous system injuries in this patient population is incompletely understood and is likely multifactorial. Therefore, in this study we wanted to determine the incidence of postoperative neurocognitive deficits and review all reported cases of neurocognitive complications in patients who have undergone arthroscopic shoulder surgery in the BCP. In addition, we wanted to define the incidence of intraoperative CDEs and investigate their relationship with postoperative neurocognitive complications.

According to our review, the incidence of postoperative neurocognitive complications after surgery in the BCP is 0.004% (1/24,701). However, this finding is based only on what has been reported; the true incidence is not known. It is also important to note that the incidence of neurocognitive deficits after many other types of surgery is not known and that surgery itself may be a risk factor for postoperative neurocognitive deficits.²⁴ In their retrospective review of 15,014 patients who underwent arthroscopic shoulder surgery in the BCP at a single institution over an 11-year period, Rohrbaugh and colleagues18 found an overall postoperative complication rate of 0.37% and a 0.0067% incidence of neurocognitive deficits. One patient in the series was given a diagnosis of ischemic stroke on the basis of neurologic deficits that occurred 24 hours after surgery. Yadeau and colleagues²⁰ found no postoperative neurocognitive complications in a mixed prospective-retrospective study of 4169 patients—3000 identified retrospectively, 1169 prospectively—who underwent arthroscopic shoulder surgery in the BCP at an ambulatory surgery center. Pin-on and colleagues¹⁹ reported on a series of 5177 orthopedic and neurosurgical patients who underwent surgery in the BCP. In those who had arthroscopic shoulder surgery, intraoperative systolic blood pressures obtained from an arterial line referenced to heart level decreased a mean (SD) of 14.4% (12.7%), whereas in those whose pressures were obtained from a noninvasive blood pressure cuff referenced to heart level decreased 19.3% (12.6%). However, the authors reported no incidence of postoperative stroke or neurologic deficits.

Although uncommon, perioperative cerebral ischemic accidents are potentially devastating for patients, their families, and the health care professionals involved. These events have tremendous economic, social, professional, and medicolegal implications, with perioperative stroke being particularly morbid. Perioperative stroke has a mortality rate of 60%, versus 15% to 46% for stroke in general.^25,26 In 2005, Pohl and Cullen⁶ published a landmark article on a series of 4 relatively healthy middle-aged patients who were at low risk for stroke but had catastrophic neurocognitive complications (including 1 death) after arthroscopic shoulder surgery in the BCP. Bhatti and Enneking³ described a case of acute postoperative vision loss and ophthalmoplegia attributed to intraoperative hypotension leading to ischemia in a patient who underwent an elective shoulder arthroscopic procedure in the BCP. These reports prompted multiple investigations into the physiologic hemodynamic changes associated with surgery in the BCP and the treatment strategies used to improve patient safety.

In the normal physiologic state, the sympathetic nervous system is activated when a person assumes the seated position. The result is increased systemic vascular resistance and heart rate alterations to maintain cardiac output and mean arterial pressure. In anesthetized patients, this response is blunted by the vasodilatory effects of intravenous and volatile anesthetics. Multiple studies have demonstrated substantial hemodynamic changes in both awake and anesthetized patients during the maneuver from the supine position to the seated position^1,27,28; these changes include diminished cardiac index, stroke volume, and arterial pressure.¹⁷ The data underscore the need for attentiveness and accurate monitoring of cerebral perfusion when the transition is made from the supine position to the BCP, particularly in the early phase of surgery and in high-risk patients.

 

Knowledge of these hemodynamic changes has led several authors to recommend additional intraoperative monitoring of cerebral perfusion. Monitoring techniques have included use of invasive blood pressure monitoring adjusted to brain level, cerebral oximetry using near infrared spectroscopy, and electroencephalography. However, the clinical relevance of intraoperative CDEs in isolation is not well understood.^1,6,7,23 In addition, cost and availability of additional advanced monitoring likely factor into why it is not more commonly used. For this patient population, the severity, frequency, and duration of desaturation that causes cerebral ischemia and the relationship with postoperative neurocognitive deficits remain undefined.

The incidence of CDEs in patients being monitored with near infrared spectroscopy while undergoing elective arthroscopic shoulder surgery in the BCP varies widely, from 0% to 80% (mean, 41%).^{1,4,7,10,12,21} Magnitude and duration of cerebral ischemia required to produce neurocognitive dysfunction in this patient population remain unidentified as well. In conscious patients, a 20% reduction in frontal lobe oxygenation is associated with clinical manifestations of cerebral hypoperfusion, such as syncope.^15,29 As none of the patients in the studies we reviewed experienced any sort of deficit, we cannot definitively state there is a correlation between CDE occurrence and neurocognitive deficit.

One limitation of our investigation is that it was a systemic review, and thus there was substantial heterogeneity in the methods and designs of the studies included in the analysis. Among the different series, there was variability in multiple aspects of the study design, including type of anesthetic, patient inclusion criteria, type of surgery, type of intraoperative cerebral perfusion monitoring, and type of neurocognitive testing. As a result, comparing the groups was difficult, and the generalizability of our findings may be limited. In addition, it is difficult to accurately establish incidence and comprehensively review these events because of the paucity of literature.

Conclusion

Neurocognitive complications after shoulder arthroscopy with the patient in the BCP are extremely rare but potentially devastating events that can affect healthy patients with no preexisting cerebrovascular risk factors. Our review indicated the incidence of permanent neurologic deficit after arthroscopy in the BCP may be as low as 0.004%. The exact etiology of such complications is not clear. Basic science research and large prospective studies are needed to identify the clinically relevant thresholds of magnitude, duration, and frequency of intraoperative CDEs in order to establish their relationship with postoperative neurocognitive complications. Such large studies may also elucidate modifiable patient-specific risk factors and establish the most sensitive, safe, and cost-effective intraoperative monitoring tools. Current literature suggests that accurate intraoperative monitoring of cerebral perfusion, alternatives to general anesthesia, and prudent use of intraoperative blood pressure control may improve patient safety.

The beach-chair position (BCP) is commonly used for both arthroscopic and open shoulder surgery. This technique positions the shoulder in an anatomical upright position, facilitating shoulder access and visualization.¹ Compared with the lateral decubitus position, the BCP also improves airway access, reduces bleeding, and lessens the risk for brachial plexus injury.²

Despite the advantages of using the BCP, there have been multiple reports of catastrophic neurologic complications, including severe brain damage and death, in relatively healthy patients without any known risk factors.^3-6 The definitive etiology of these complications remains unclear, but it has been hypothesized that BCP use may be an independent risk factor for cerebrovascular ischemia,^1,5-16 as the upright position can cause hypotension leading to increased risk for cerebral hypoperfusion.^7-11,17 Reducing cerebral perfusion pressure below critical thresholds may result in permanent neurologic injury.^4-6,14 Therefore, monitoring of cerebral perfusion and optimization of intraoperative cerebral oxygenation have been recommended to help avoid potential neurologic complications. However, a direct relationship between intraoperative cerebral desaturation events (CDEs) and postoperative neurocognitive deficits has not been definitively established.^1,9-12

To put into perspective the importance of detecting and preventing CDEs and neurologic complications, we can consider the incidence of fatal pulmonary embolism associated with total joint arthroplasty. Although the incidence is very low, about 0.1% to 2.0%, some form of venous thromboembolism prophylaxis is the standard of care for helping prevent this serious complication. Similarly, catastrophic neurologic complications of upright shoulder arthroscopy are very rare, but it is still important to consider measures that help minimize them.

We reviewed the literature for the incidence of postoperative neurocognitive deficits, number of reported neurocognitive complications, and incidence of intraoperative CDEs in patients who underwent arthroscopic shoulder surgery in the BCP.

Methods

Dr. Salazar and Dr. Hazel independently searched the Medline, Cochrane, and Embase databases for case series, prospective studies, and cohort studies that reported neurocognitive complications associated with the BCP and the incidence of intraoperative CDEs. The authors used beach chair, desaturation, near infrared spectroscopy, and shoulder as medical subject headings (MeSH). In addition, bibliographies of retrieved articles were checked for studies that the search terms may have missed. Eighty-one publications were identified and reviewed for possible inclusion.

Next, the same 2 authors reviewed the titles and abstracts for relevance and determined which articles had potential to contribute to the study. Only English-language publications were considered for inclusion. To review the incidence of postoperative neurocognitive deficits, we included only those studies with more than 25 patients, documentation of postoperative complications, and arthroscopic shoulder surgery performed with the patient in the seated, semi-upright, or BCP. Only studies with at least 25 patients were used in order to increase the power and improve the level of evidence. To review reported cases of neurocognitive complications, we included all relevant case reports and case series. To review the incidence of intraoperative CDEs and investigate their relationship with postoperative neurocognitive deficits, we included studies that reported on use of intraoperative cerebral perfusion monitoring. Modalities used in these studies included near infrared spectroscopy, electroencephalography, and invasive blood pressure monitoring calculated at the brain level. Studies were excluded if they did not involve arthroscopic shoulder surgery or were not conducted with human subjects.

Information recorded for each study included general information such as author and publication year, type of study, number of patients enrolled, type of intraoperative monitoring, anesthesia protocol, number of patients with CDEs, and number of patients with neurocognitive complications after surgery.

Results

Our search identified 81 publications for potential inclusion. Our first aim was to identify the overall incidence of reported neurocognitive deficits after arthroscopic shoulder surgery with the patient in the BCP. We identified 10 studies (Table 1) that met the inclusion criteria. Among the 24,701 patients in these 10 studies, there was only 1 reported case of neurocognitive deficit after surgery, in a mixed prospective-retrospective study of 15,014 cases by Rohrbaugh and colleagues.18 The deficit they reported was an ischemic cerebral vascular accident. The 0.0067% incidence in their study demonstrates how rare the complication is. Two large retrospective studies (Ns = 4169 and 5177 patients) found no postoperative neurocognitive complications.^19,20 Only 3 studies performed formal postoperative cognitive testing. Salazar and colleagues²¹ used the Repeatable Battery for the Assessment of Neuropsychological Status before and after surgery, and Gillespie and colleagues⁸ and Lee and colleagues¹⁰ used the Mini–Mental State Examination before and after surgery. Total incidence of reported neurocognitive deficits from our review was 0.004% (1/24,701).

Our second aim was to review all reported cases of neurocognitive complications after arthroscopic shoulder surgery with the patient in the BCP. We identified 4 publications that fit our inclusion criteria (Table 2). Pohl and Cullen6 described 4 cases of ischemic brain injury after arthroscopic shoulder surgery with the patient in the BCP. Age range was 47 to 57 years. Specific intraoperative cerebral monitoring was not used. However, these patients had several episodes of intraoperative hypotension (systolic blood pressures, 80-90 mm Hg), measured with a traditional blood pressure cuff on the arm. In general, these patients had minimal cerebrovascular risk factors and no known preexisting cerebrovascular disease. Drummond and colleagues²² described an ischemic stroke in a 50-year-old man after arthroscopic subacromial decompression and open rotator cuff repair that resulted in unresolved right hemiplegia. Subsequent diagnostic investigation revealed an asymmetry of the circle of Willis resulting in limited flow to the left anterior and middle cerebral artery distributions. Bhatti and Enneking³ reported the case of a 64-year-old man who lost vision in the right eye immediately after arthroscopic rotator cuff repair. His vision improved spontaneously the next morning and continued to improve over the next 6 months—he regained 20/20 vision with some residual optic neuropathy.

 

Our third aim was to determine the incidence of intraoperative CDEs during arthroscopic shoulder surgery with the patient in the BCP. Incidence of CDEs varied widely among the 7 studies reviewed (Table 3). Minimum incidence of intraoperative CDE was 0% in a cohort of 30 patients,¹ and maximum incidence was 80% in a study of 61 patients,¹² all of whom underwent elective arthroscopic shoulder surgery in the BCP. Although there was wide variability in CDE incidence, the studies were consistent with respect to their definition of a CDE. Most authors used a decrease in regional cerebral tissue oxygen saturation of 20% or more from baseline, or an absolute value up to 55%, to define a CDE. None of the 7 studies reviewed reported a clinically significant adverse neurocognitive event.

Discussion

Of concern, there have been several surveys, case reports, and small case series of previously healthy patients who had no known risk factors, underwent arthroscopic shoulder surgery in the BCP, and developed unanticipated postoperative neurologic complications.^4-6,14 Beach-chair positioning during surgical procedures has been implicated as a contributing factor leading to cerebral hypoperfusion with potential for cerebral ischemia.^1,12,23 These changes in cerebral perfusion pressure are thought to be the major determinant of poor neurologic outcomes. Such reports have exposed the potential need for heightened vigilance, alternative anesthesia techniques, and improved monitoring, though the exact etiology of the central nervous system injuries in this patient population is incompletely understood and is likely multifactorial. Therefore, in this study we wanted to determine the incidence of postoperative neurocognitive deficits and review all reported cases of neurocognitive complications in patients who have undergone arthroscopic shoulder surgery in the BCP. In addition, we wanted to define the incidence of intraoperative CDEs and investigate their relationship with postoperative neurocognitive complications.

According to our review, the incidence of postoperative neurocognitive complications after surgery in the BCP is 0.004% (1/24,701). However, this finding is based only on what has been reported; the true incidence is not known. It is also important to note that the incidence of neurocognitive deficits after many other types of surgery is not known and that surgery itself may be a risk factor for postoperative neurocognitive deficits.²⁴ In their retrospective review of 15,014 patients who underwent arthroscopic shoulder surgery in the BCP at a single institution over an 11-year period, Rohrbaugh and colleagues18 found an overall postoperative complication rate of 0.37% and a 0.0067% incidence of neurocognitive deficits. One patient in the series was given a diagnosis of ischemic stroke on the basis of neurologic deficits that occurred 24 hours after surgery. Yadeau and colleagues²⁰ found no postoperative neurocognitive complications in a mixed prospective-retrospective study of 4169 patients—3000 identified retrospectively, 1169 prospectively—who underwent arthroscopic shoulder surgery in the BCP at an ambulatory surgery center. Pin-on and colleagues¹⁹ reported on a series of 5177 orthopedic and neurosurgical patients who underwent surgery in the BCP. In those who had arthroscopic shoulder surgery, intraoperative systolic blood pressures obtained from an arterial line referenced to heart level decreased a mean (SD) of 14.4% (12.7%), whereas in those whose pressures were obtained from a noninvasive blood pressure cuff referenced to heart level decreased 19.3% (12.6%). However, the authors reported no incidence of postoperative stroke or neurologic deficits.

Although uncommon, perioperative cerebral ischemic accidents are potentially devastating for patients, their families, and the health care professionals involved. These events have tremendous economic, social, professional, and medicolegal implications, with perioperative stroke being particularly morbid. Perioperative stroke has a mortality rate of 60%, versus 15% to 46% for stroke in general.^25,26 In 2005, Pohl and Cullen⁶ published a landmark article on a series of 4 relatively healthy middle-aged patients who were at low risk for stroke but had catastrophic neurocognitive complications (including 1 death) after arthroscopic shoulder surgery in the BCP. Bhatti and Enneking³ described a case of acute postoperative vision loss and ophthalmoplegia attributed to intraoperative hypotension leading to ischemia in a patient who underwent an elective shoulder arthroscopic procedure in the BCP. These reports prompted multiple investigations into the physiologic hemodynamic changes associated with surgery in the BCP and the treatment strategies used to improve patient safety.

In the normal physiologic state, the sympathetic nervous system is activated when a person assumes the seated position. The result is increased systemic vascular resistance and heart rate alterations to maintain cardiac output and mean arterial pressure. In anesthetized patients, this response is blunted by the vasodilatory effects of intravenous and volatile anesthetics. Multiple studies have demonstrated substantial hemodynamic changes in both awake and anesthetized patients during the maneuver from the supine position to the seated position^1,27,28; these changes include diminished cardiac index, stroke volume, and arterial pressure.¹⁷ The data underscore the need for attentiveness and accurate monitoring of cerebral perfusion when the transition is made from the supine position to the BCP, particularly in the early phase of surgery and in high-risk patients.

 

Knowledge of these hemodynamic changes has led several authors to recommend additional intraoperative monitoring of cerebral perfusion. Monitoring techniques have included use of invasive blood pressure monitoring adjusted to brain level, cerebral oximetry using near infrared spectroscopy, and electroencephalography. However, the clinical relevance of intraoperative CDEs in isolation is not well understood.^1,6,7,23 In addition, cost and availability of additional advanced monitoring likely factor into why it is not more commonly used. For this patient population, the severity, frequency, and duration of desaturation that causes cerebral ischemia and the relationship with postoperative neurocognitive deficits remain undefined.

The incidence of CDEs in patients being monitored with near infrared spectroscopy while undergoing elective arthroscopic shoulder surgery in the BCP varies widely, from 0% to 80% (mean, 41%).^{1,4,7,10,12,21} Magnitude and duration of cerebral ischemia required to produce neurocognitive dysfunction in this patient population remain unidentified as well. In conscious patients, a 20% reduction in frontal lobe oxygenation is associated with clinical manifestations of cerebral hypoperfusion, such as syncope.^15,29 As none of the patients in the studies we reviewed experienced any sort of deficit, we cannot definitively state there is a correlation between CDE occurrence and neurocognitive deficit.

One limitation of our investigation is that it was a systemic review, and thus there was substantial heterogeneity in the methods and designs of the studies included in the analysis. Among the different series, there was variability in multiple aspects of the study design, including type of anesthetic, patient inclusion criteria, type of surgery, type of intraoperative cerebral perfusion monitoring, and type of neurocognitive testing. As a result, comparing the groups was difficult, and the generalizability of our findings may be limited. In addition, it is difficult to accurately establish incidence and comprehensively review these events because of the paucity of literature.

Conclusion

Neurocognitive complications after shoulder arthroscopy with the patient in the BCP are extremely rare but potentially devastating events that can affect healthy patients with no preexisting cerebrovascular risk factors. Our review indicated the incidence of permanent neurologic deficit after arthroscopy in the BCP may be as low as 0.004%. The exact etiology of such complications is not clear. Basic science research and large prospective studies are needed to identify the clinically relevant thresholds of magnitude, duration, and frequency of intraoperative CDEs in order to establish their relationship with postoperative neurocognitive complications. Such large studies may also elucidate modifiable patient-specific risk factors and establish the most sensitive, safe, and cost-effective intraoperative monitoring tools. Current literature suggests that accurate intraoperative monitoring of cerebral perfusion, alternatives to general anesthesia, and prudent use of intraoperative blood pressure control may improve patient safety.

The beach-chair position (BCP) is commonly used for both arthroscopic and open shoulder surgery. This technique positions the shoulder in an anatomical upright position, facilitating shoulder access and visualization.¹ Compared with the lateral decubitus position, the BCP also improves airway access, reduces bleeding, and lessens the risk for brachial plexus injury.²

Despite the advantages of using the BCP, there have been multiple reports of catastrophic neurologic complications, including severe brain damage and death, in relatively healthy patients without any known risk factors.^3-6 The definitive etiology of these complications remains unclear, but it has been hypothesized that BCP use may be an independent risk factor for cerebrovascular ischemia,^1,5-16 as the upright position can cause hypotension leading to increased risk for cerebral hypoperfusion.^7-11,17 Reducing cerebral perfusion pressure below critical thresholds may result in permanent neurologic injury.^4-6,14 Therefore, monitoring of cerebral perfusion and optimization of intraoperative cerebral oxygenation have been recommended to help avoid potential neurologic complications. However, a direct relationship between intraoperative cerebral desaturation events (CDEs) and postoperative neurocognitive deficits has not been definitively established.^1,9-12

To put into perspective the importance of detecting and preventing CDEs and neurologic complications, we can consider the incidence of fatal pulmonary embolism associated with total joint arthroplasty. Although the incidence is very low, about 0.1% to 2.0%, some form of venous thromboembolism prophylaxis is the standard of care for helping prevent this serious complication. Similarly, catastrophic neurologic complications of upright shoulder arthroscopy are very rare, but it is still important to consider measures that help minimize them.

We reviewed the literature for the incidence of postoperative neurocognitive deficits, number of reported neurocognitive complications, and incidence of intraoperative CDEs in patients who underwent arthroscopic shoulder surgery in the BCP.

Methods

Dr. Salazar and Dr. Hazel independently searched the Medline, Cochrane, and Embase databases for case series, prospective studies, and cohort studies that reported neurocognitive complications associated with the BCP and the incidence of intraoperative CDEs. The authors used beach chair, desaturation, near infrared spectroscopy, and shoulder as medical subject headings (MeSH). In addition, bibliographies of retrieved articles were checked for studies that the search terms may have missed. Eighty-one publications were identified and reviewed for possible inclusion.

Next, the same 2 authors reviewed the titles and abstracts for relevance and determined which articles had potential to contribute to the study. Only English-language publications were considered for inclusion. To review the incidence of postoperative neurocognitive deficits, we included only those studies with more than 25 patients, documentation of postoperative complications, and arthroscopic shoulder surgery performed with the patient in the seated, semi-upright, or BCP. Only studies with at least 25 patients were used in order to increase the power and improve the level of evidence. To review reported cases of neurocognitive complications, we included all relevant case reports and case series. To review the incidence of intraoperative CDEs and investigate their relationship with postoperative neurocognitive deficits, we included studies that reported on use of intraoperative cerebral perfusion monitoring. Modalities used in these studies included near infrared spectroscopy, electroencephalography, and invasive blood pressure monitoring calculated at the brain level. Studies were excluded if they did not involve arthroscopic shoulder surgery or were not conducted with human subjects.

Information recorded for each study included general information such as author and publication year, type of study, number of patients enrolled, type of intraoperative monitoring, anesthesia protocol, number of patients with CDEs, and number of patients with neurocognitive complications after surgery.

Results

Our search identified 81 publications for potential inclusion. Our first aim was to identify the overall incidence of reported neurocognitive deficits after arthroscopic shoulder surgery with the patient in the BCP. We identified 10 studies (Table 1) that met the inclusion criteria. Among the 24,701 patients in these 10 studies, there was only 1 reported case of neurocognitive deficit after surgery, in a mixed prospective-retrospective study of 15,014 cases by Rohrbaugh and colleagues.18 The deficit they reported was an ischemic cerebral vascular accident. The 0.0067% incidence in their study demonstrates how rare the complication is. Two large retrospective studies (Ns = 4169 and 5177 patients) found no postoperative neurocognitive complications.^19,20 Only 3 studies performed formal postoperative cognitive testing. Salazar and colleagues²¹ used the Repeatable Battery for the Assessment of Neuropsychological Status before and after surgery, and Gillespie and colleagues⁸ and Lee and colleagues¹⁰ used the Mini–Mental State Examination before and after surgery. Total incidence of reported neurocognitive deficits from our review was 0.004% (1/24,701).

Our second aim was to review all reported cases of neurocognitive complications after arthroscopic shoulder surgery with the patient in the BCP. We identified 4 publications that fit our inclusion criteria (Table 2). Pohl and Cullen6 described 4 cases of ischemic brain injury after arthroscopic shoulder surgery with the patient in the BCP. Age range was 47 to 57 years. Specific intraoperative cerebral monitoring was not used. However, these patients had several episodes of intraoperative hypotension (systolic blood pressures, 80-90 mm Hg), measured with a traditional blood pressure cuff on the arm. In general, these patients had minimal cerebrovascular risk factors and no known preexisting cerebrovascular disease. Drummond and colleagues²² described an ischemic stroke in a 50-year-old man after arthroscopic subacromial decompression and open rotator cuff repair that resulted in unresolved right hemiplegia. Subsequent diagnostic investigation revealed an asymmetry of the circle of Willis resulting in limited flow to the left anterior and middle cerebral artery distributions. Bhatti and Enneking³ reported the case of a 64-year-old man who lost vision in the right eye immediately after arthroscopic rotator cuff repair. His vision improved spontaneously the next morning and continued to improve over the next 6 months—he regained 20/20 vision with some residual optic neuropathy.

 

Our third aim was to determine the incidence of intraoperative CDEs during arthroscopic shoulder surgery with the patient in the BCP. Incidence of CDEs varied widely among the 7 studies reviewed (Table 3). Minimum incidence of intraoperative CDE was 0% in a cohort of 30 patients,¹ and maximum incidence was 80% in a study of 61 patients,¹² all of whom underwent elective arthroscopic shoulder surgery in the BCP. Although there was wide variability in CDE incidence, the studies were consistent with respect to their definition of a CDE. Most authors used a decrease in regional cerebral tissue oxygen saturation of 20% or more from baseline, or an absolute value up to 55%, to define a CDE. None of the 7 studies reviewed reported a clinically significant adverse neurocognitive event.

Discussion

Of concern, there have been several surveys, case reports, and small case series of previously healthy patients who had no known risk factors, underwent arthroscopic shoulder surgery in the BCP, and developed unanticipated postoperative neurologic complications.^4-6,14 Beach-chair positioning during surgical procedures has been implicated as a contributing factor leading to cerebral hypoperfusion with potential for cerebral ischemia.^1,12,23 These changes in cerebral perfusion pressure are thought to be the major determinant of poor neurologic outcomes. Such reports have exposed the potential need for heightened vigilance, alternative anesthesia techniques, and improved monitoring, though the exact etiology of the central nervous system injuries in this patient population is incompletely understood and is likely multifactorial. Therefore, in this study we wanted to determine the incidence of postoperative neurocognitive deficits and review all reported cases of neurocognitive complications in patients who have undergone arthroscopic shoulder surgery in the BCP. In addition, we wanted to define the incidence of intraoperative CDEs and investigate their relationship with postoperative neurocognitive complications.

According to our review, the incidence of postoperative neurocognitive complications after surgery in the BCP is 0.004% (1/24,701). However, this finding is based only on what has been reported; the true incidence is not known. It is also important to note that the incidence of neurocognitive deficits after many other types of surgery is not known and that surgery itself may be a risk factor for postoperative neurocognitive deficits.²⁴ In their retrospective review of 15,014 patients who underwent arthroscopic shoulder surgery in the BCP at a single institution over an 11-year period, Rohrbaugh and colleagues18 found an overall postoperative complication rate of 0.37% and a 0.0067% incidence of neurocognitive deficits. One patient in the series was given a diagnosis of ischemic stroke on the basis of neurologic deficits that occurred 24 hours after surgery. Yadeau and colleagues²⁰ found no postoperative neurocognitive complications in a mixed prospective-retrospective study of 4169 patients—3000 identified retrospectively, 1169 prospectively—who underwent arthroscopic shoulder surgery in the BCP at an ambulatory surgery center. Pin-on and colleagues¹⁹ reported on a series of 5177 orthopedic and neurosurgical patients who underwent surgery in the BCP. In those who had arthroscopic shoulder surgery, intraoperative systolic blood pressures obtained from an arterial line referenced to heart level decreased a mean (SD) of 14.4% (12.7%), whereas in those whose pressures were obtained from a noninvasive blood pressure cuff referenced to heart level decreased 19.3% (12.6%). However, the authors reported no incidence of postoperative stroke or neurologic deficits.

Although uncommon, perioperative cerebral ischemic accidents are potentially devastating for patients, their families, and the health care professionals involved. These events have tremendous economic, social, professional, and medicolegal implications, with perioperative stroke being particularly morbid. Perioperative stroke has a mortality rate of 60%, versus 15% to 46% for stroke in general.^25,26 In 2005, Pohl and Cullen⁶ published a landmark article on a series of 4 relatively healthy middle-aged patients who were at low risk for stroke but had catastrophic neurocognitive complications (including 1 death) after arthroscopic shoulder surgery in the BCP. Bhatti and Enneking³ described a case of acute postoperative vision loss and ophthalmoplegia attributed to intraoperative hypotension leading to ischemia in a patient who underwent an elective shoulder arthroscopic procedure in the BCP. These reports prompted multiple investigations into the physiologic hemodynamic changes associated with surgery in the BCP and the treatment strategies used to improve patient safety.

In the normal physiologic state, the sympathetic nervous system is activated when a person assumes the seated position. The result is increased systemic vascular resistance and heart rate alterations to maintain cardiac output and mean arterial pressure. In anesthetized patients, this response is blunted by the vasodilatory effects of intravenous and volatile anesthetics. Multiple studies have demonstrated substantial hemodynamic changes in both awake and anesthetized patients during the maneuver from the supine position to the seated position^1,27,28; these changes include diminished cardiac index, stroke volume, and arterial pressure.¹⁷ The data underscore the need for attentiveness and accurate monitoring of cerebral perfusion when the transition is made from the supine position to the BCP, particularly in the early phase of surgery and in high-risk patients.

 

Knowledge of these hemodynamic changes has led several authors to recommend additional intraoperative monitoring of cerebral perfusion. Monitoring techniques have included use of invasive blood pressure monitoring adjusted to brain level, cerebral oximetry using near infrared spectroscopy, and electroencephalography. However, the clinical relevance of intraoperative CDEs in isolation is not well understood.^1,6,7,23 In addition, cost and availability of additional advanced monitoring likely factor into why it is not more commonly used. For this patient population, the severity, frequency, and duration of desaturation that causes cerebral ischemia and the relationship with postoperative neurocognitive deficits remain undefined.

The incidence of CDEs in patients being monitored with near infrared spectroscopy while undergoing elective arthroscopic shoulder surgery in the BCP varies widely, from 0% to 80% (mean, 41%).^{1,4,7,10,12,21} Magnitude and duration of cerebral ischemia required to produce neurocognitive dysfunction in this patient population remain unidentified as well. In conscious patients, a 20% reduction in frontal lobe oxygenation is associated with clinical manifestations of cerebral hypoperfusion, such as syncope.^15,29 As none of the patients in the studies we reviewed experienced any sort of deficit, we cannot definitively state there is a correlation between CDE occurrence and neurocognitive deficit.

One limitation of our investigation is that it was a systemic review, and thus there was substantial heterogeneity in the methods and designs of the studies included in the analysis. Among the different series, there was variability in multiple aspects of the study design, including type of anesthetic, patient inclusion criteria, type of surgery, type of intraoperative cerebral perfusion monitoring, and type of neurocognitive testing. As a result, comparing the groups was difficult, and the generalizability of our findings may be limited. In addition, it is difficult to accurately establish incidence and comprehensively review these events because of the paucity of literature.

Conclusion

Neurocognitive complications after shoulder arthroscopy with the patient in the BCP are extremely rare but potentially devastating events that can affect healthy patients with no preexisting cerebrovascular risk factors. Our review indicated the incidence of permanent neurologic deficit after arthroscopy in the BCP may be as low as 0.004%. The exact etiology of such complications is not clear. Basic science research and large prospective studies are needed to identify the clinically relevant thresholds of magnitude, duration, and frequency of intraoperative CDEs in order to establish their relationship with postoperative neurocognitive complications. Such large studies may also elucidate modifiable patient-specific risk factors and establish the most sensitive, safe, and cost-effective intraoperative monitoring tools. Current literature suggests that accurate intraoperative monitoring of cerebral perfusion, alternatives to general anesthesia, and prudent use of intraoperative blood pressure control may improve patient safety.

Upper extremity injuries are very common in pitchers in amateur and professional baseball. The vast majority involving labral or rotator cuff pathology.^1-3 While uncommon, injuries to the latissimus dorsi (LD) (Figure) and teres major (TM) have been reported in Major League Baseball (MLB) pitchers.⁴ Jobe and colleagues⁵ demonstrated the role of the LD during the various phases of pitching. The LD is most active during the acceleration phase and remains active during the deceleration phase and follow-through.⁶ Anatomically, the TM lies posterior to the LD separated by bursal tissue. The tendon fibers converge and unite along their lower borders, leading to a synergistic mechanism of action.

Due to the rarity of LD and TM injuries, literature on the pathology and appropriate treatments for these injuries is limited. The goal of this review is to present the current literature on professional baseball players who have undergone either nonsurgical treatment or surgery for LD and TM strains and/or avulsion injuries. This review will ultimately assist clinicians when deciding on the optimal treatment method for professional baseball players.

Methods

We performed an extensive Medline database search with the following search algorithm: ([latissimus OR latissimus dorsi OR teres major] AND baseball). The search returned 20 citations. Inclusion criteria consisted of clinical studies that focused on professional baseball pitchers with TM and/or LD injuries that underwent either conservative nonsurgical treatment or surgical repair. There was no exclusion based on the type of injury present, such as avulsion vs strain. Any study with amateur athletes or athletes from other sports such as handball or rugby were excluded. Due to the limited amount of data available, the majority of included studies were case reports and case series.

Based on these parameters, 5 articles met criteria for inclusion. Of the 5 included studies, 3 were case reports and 2 were case series. From the eligible articles, the following information was obtained: publication year, sample size, mean age, mean follow-up duration, type of treatment (conservative vs surgical), ability to return to original level of play, time required to return to original form, and complications (Tables 1, 2).

Results

Nonoperative Management

Four of the 5 included studies implemented only conservative therapy for their patients.^4,7-9 The average duration these patients were followed for during treatment and rehabilitation was 26.3 months. Malcolm and colleagues⁷ followed patients for 8 months, the shortest length among the 4 conservative studies in this review. Leland and colleagues8 followed patients for 17 months, and Nagda and colleagues⁹ had the longest length of observation of 36 months (range 12 to 82 months).Schickendantz and colleagues⁴ followed patients for >12 months, but the exact duration was not specified. In order to calculate the average duration of observation, each patient was assigned a duration of 12 months.

Of the 30 patients included in this review, 29 were treated conservatively. All of the included studies consisted of male patients. The mean age was 26.8 years (range 22 to 28.1 years). Of the 29 injuries treated conservatively, there were 2 LD tendon avulsions, 4 TM tendon avulsions, 1 LD and TM tendon avulsion, 7 LD intramuscular strains, 9 TM intramuscular strains, and 6 LD and TM intramuscular strains.

Treatment Protocol

The various treatment and rehabilitation programs used for the conservative patient population all followed a similar pathway. After initial injury, a rest period focused on stretching was implemented. Patients were started on steroid or anti-inflammatory medications, cryotherapy, or other therapeutic modalities. Once pain-free and full range of motion was achieved, patients began the strength and throwing components of the rehabilitation program. Reoccurrence of symptoms would halt the throwing component of the rehabilitation program until symptoms improved. Patients were progressed through a return-to-throw program and once they could throw off the mound and achieve their preinjury velocity, strength, and range of motion, they were cleared to return to competitive pitching.

In the senior author’s (MSS) practice, all throwers are managed with the same nonoperative protocol.⁴ Initial treatment consists of short periods of rest and symptom control via the application of cryotherapy, among other modalities. Restoration of preinjury range of motion is achieved with active-assisted stretching exercises. As range of motion begins approaching pre-injury levels, strength training is initiated with isometric strengthening of the LD and TM progressing to resistance exercises. Exercising the abdominal core, strengthening the lower body, and cardiovascular conditioning are focal points of the rehabilitation period. Once patients regain preinjury shoulder strength and range of motion without pain, they begin a throwing program that consists of 4 weeks of long toss followed by 2 weeks of throwing from the pitching mound. After completion of the throwing program, the patient is allowed to return to competitive pitching. For patients who did not suffer season-ending injury, the average time required to return to play was 99.8 days (range 72.3 to 182.6 days).

 

Complications and Reinjury

The patients in Leland and colleagues⁸ and Malcolm and colleagues⁷ did not suffer any complications or reinjuries. In Schickendantz and colleagues⁴, all but 3 of the 10 patients were able to return to full speed pitching by 3 months. The other 3 required 4, 6, and 10 months. The patient that required 10 months tore both his LD and TM and the patient that required 6 months tore his TM and was never able to regain his pre-injury throwing velocity. None of the TM tears had a recurrence, while 1 LD tear had a recurrence of injury 6 months after returning to competitive pitching. This patient was successfully treated with 6 weeks of conservative rest and rehabilitation.

In Nagda and colleagues⁹, 2 athletes suffered injury recurrence. One athlete with a LD strain suffered 2 subsequent LD strains, 4 months and 1 year after initial injury. The other athlete with a LD avulsion suffered a subsequent TM avulsion 13 months after initial injury. One pitcher who had an LD and TM strain suffered a superior labrum anterior and posterior (SLAP) tear and was never able to return to his prior level of play.

Surgical Treatment

Only 1 of the 5 included studies utilized surgical repair for their patient.¹⁰ The single patient suffered an avulsion injury of the distal LD tendon and its insertion on the humerus. The LD tendon was retracted approximately 5 cm from the distal humeral insertion. The TM was not involved. Eight days post-injury, the patient underwent surgical repair.¹¹ Postoperatively, the patient started passive range of motion after 2 weeks and active range of motion after 6 weeks. He started throwing at 12 weeks and returned to play at 30 weeks after he had returned to his preinjury form in regards to muscle strength, pitch control, and velocity. The patient was able to resume pitching at a high level in MLB.

Discussion

Overhand throwing athletes, especially professional baseball players, have to constantly deal with a variety of shoulder injuries.^12,13 Currently, there is minimal literature on isolated TM and LD injuries. As a result, there is still debate about the optimal treatment method for these injuries, especially in athletes who compete at the highest level. In order to treat isolated injuries of these muscles, it is important to understand their anatomic relationship, as these 2 muscles are intimately associated. The LD originates from the thoracolumbar spine and inserts on the proximal humerus between the pectoralis<hl name="2"/> major and TM tendons. The TM originates from the scapula and, similar to the LD, inserts on the proximal humerus. In an anatomic study, the TM tendon inserted into the LD tendon before its humeral insertion in the majority of cadavers.^14,15

The LD is responsible for extension, adduction, and internal rotation of the humerus. The TM, while not as extensively studied, is believed to also contribute to extension, adduction, and internal rotation of the humerus.¹⁶ As Jobe and colleagues⁵ demonstrated, the LD is vital during the acceleration phase of pitching. While they were unable to make any conclusions about the role of the TM during the pitching cycle, it is reasonable to hypothesize that these 2 muscles work together. While it is thought that these 2 muscles work as a unit, it is significant to note that a professional pitcher can sustain an isolated injury to the TM without injury to the LD, and vice versa. This questions whether these 2 muscles work more independently than once thought. One hypothesis is that the physical size of the LD provides protection from injuries that the smaller TM cannot overcome. This is a potential area of further research.

The most common findings in patients with TM injuries include swelling, bruising, tenderness of the proximal arm, and limitations of shoulder range of motion in abduction, flexion, and external rotation. There is also weakness when resistance is applied against internal rotation and extension. Similar to the TM, common findings in patients with LD injuries include pain in the posterior shoulder, bruising, and weakness when resistance is applied against internal rotation of the shoulder. Pitchers are often able to pinpoint the occurrence of their acute pain during a specific time in the game. They commonly experience a pulling sensation and sometimes even feel a “pop” in their shoulder followed by an acute onset of pain and stiffness in the posterior aspect of the axilla. These injuries seem to be associated with the pitcher throwing a “breaking ball,” a pitch that requires greater shoulder rotation since it changes trajectory while traveling towards home plate. Despite the clear role of the LD and hypothesized role of the TM in the pitching sequence, there has been limited research on the optimal treatment of isolated injuries of these muscles in MLB pitchers. The majority of studies in this review opted for conservative treatment for both LD and TM injuries. The only study that presented a surgical option was for a LD avulsion injury.

 

Athletes undergoing either conservative or surgical treatment required a significant period of recovery and rehabilitation before they were able to compete at the professional level. In Leland and colleagues⁸, it took about 10 to 12 weeks of rehabilitation for both pitchers to return to pitching against competition. In Schickendantz and colleagues⁴, barring any complications or injury recurrence, it took patients 12 weeks to return to their preinjury level. In Malcolm and colleagues⁷, magnetic resonance imaging after 8 weeks showed marked recovery, and shortly after the pitcher was able to return to the pitching rotation. In Nagda and colleagues⁹, the time lost to injury ranged from 7 weeks to an entire season. Of the 9 pitchers who were lost for the season, 6 had avulsion injuries. The other 3 consisted of an LD strain, TM strain, and LD plus TM strain.⁹ In this study, it seems that avulsion injuries had a more significant impact on patient recovery. On average, it took 35.6 days after injury for players to begin throwing. In contrast, it took an average of 65.5 days after an avulsion injury for players to begin throwing. Ellman and colleagues¹⁰ included the only surgically repaired injury, and it was for an avulsion of the LD tendon. In the surgical case, it took slightly longer for the pitcher to return to preinjury form. It took him 12 to 16 weeks to begin light throwing and his full return to pitching took about 20 to 30 weeks. Since muscle strains and tendon avulsions are significantly different injuries in regards to the type of soft tissue damage and healing potential, they may require different treatment strategies. An avulsion injury may require more aggressive intervention, whereas a strain may only require conservative rehabilitation. Ultimately, there does not seem to be a significant benefit of one treatment option compared to the other. The majority of conservatively managed pitchers were able to return to previous form in a reasonable time frame. While each rehabilitation protocol was slightly different, multiple studies advocated for rehab programs that centered around the following goals: slowly progressing pitchers to light throwing once their pain resolved, followed by long throwing, then throwing off of the mound, and finally returning to competitive pitching. It is important to discuss with patients that rehabilitation generally takes 12 to 16 weeks before they are able to fully return to pitching against competition and that rest should immediately follow any recurrence of pain or stiffness. Once those symptoms resolve, patients may continue the rehabilitation protocol.

As with any form of treatment, there are risks involved. This holds true for both conservative and nonconservative therapy for LD and TM injuries. One risk of nonoperative treatment of an LD avulsion is the development of strength deficits in the muscle.¹⁷ While this deficit may go unnoticed in a recreational athlete, it may be more pronounced in a professional athlete, especially since the LD of a professional baseball pitcher is more active on electromyography during the acceleration phase of the pitching cycle compared to a recreational athlete.¹⁸ Another risk of conservative treatment of an LD avulsion is jeopardizing the potential for future surgery. As a result, some advocate for early surgical intervention of an acute LD avulsion.^19,20 Others, however, recommend conservative management with subsequent surgical intervention if conservative measures fail. One caveat is that surgical intervention to restore the original anatomy may become difficult after a certain period of time due to the buildup of scar tissue. Surgical intervention also has associated risks, such as nerve injury, infection, vascular damage, persistent pain, and the buildup of large amounts of scar tissue. It is important to discuss these risks with patients when deciding on a treatment option.

LD and TM avulsion and tears typically present after an acute event in throwing athletes. There are a number of case reports published that demonstrate successful outcomes with both nonoperative management²¹ and operative repair of LD injuries in non-throwing athletes such as competitive water skiers,^22,23 steer wrestlers,²⁴ professional wrestlers,²⁵ and recreational rock climbers.²⁶ The 5 studies included in this review were the first ones to present LD and TM injuries in MLB pitchers. They discussed the outcomes of mainly conservative and surgical management of LD and TM avulsion and tears. Unfortunately, there remains a limited number of cases on the treatment of these injuries in highly competitive throwing athletes. Further research is required to elucidate the advantages and disadvantages of operative vs nonoperative treatment. The goal of this review is to provide clinicians with a concise summary of the current literature so that they may offer some evidence to their patients when discussing appropriate treatment plans.

Upper extremity injuries are very common in pitchers in amateur and professional baseball. The vast majority involving labral or rotator cuff pathology.^1-3 While uncommon, injuries to the latissimus dorsi (LD) (Figure) and teres major (TM) have been reported in Major League Baseball (MLB) pitchers.⁴ Jobe and colleagues⁵ demonstrated the role of the LD during the various phases of pitching. The LD is most active during the acceleration phase and remains active during the deceleration phase and follow-through.⁶ Anatomically, the TM lies posterior to the LD separated by bursal tissue. The tendon fibers converge and unite along their lower borders, leading to a synergistic mechanism of action.

Due to the rarity of LD and TM injuries, literature on the pathology and appropriate treatments for these injuries is limited. The goal of this review is to present the current literature on professional baseball players who have undergone either nonsurgical treatment or surgery for LD and TM strains and/or avulsion injuries. This review will ultimately assist clinicians when deciding on the optimal treatment method for professional baseball players.

Methods

We performed an extensive Medline database search with the following search algorithm: ([latissimus OR latissimus dorsi OR teres major] AND baseball). The search returned 20 citations. Inclusion criteria consisted of clinical studies that focused on professional baseball pitchers with TM and/or LD injuries that underwent either conservative nonsurgical treatment or surgical repair. There was no exclusion based on the type of injury present, such as avulsion vs strain. Any study with amateur athletes or athletes from other sports such as handball or rugby were excluded. Due to the limited amount of data available, the majority of included studies were case reports and case series.

Based on these parameters, 5 articles met criteria for inclusion. Of the 5 included studies, 3 were case reports and 2 were case series. From the eligible articles, the following information was obtained: publication year, sample size, mean age, mean follow-up duration, type of treatment (conservative vs surgical), ability to return to original level of play, time required to return to original form, and complications (Tables 1, 2).

Results

Nonoperative Management

Four of the 5 included studies implemented only conservative therapy for their patients.^4,7-9 The average duration these patients were followed for during treatment and rehabilitation was 26.3 months. Malcolm and colleagues⁷ followed patients for 8 months, the shortest length among the 4 conservative studies in this review. Leland and colleagues8 followed patients for 17 months, and Nagda and colleagues⁹ had the longest length of observation of 36 months (range 12 to 82 months).Schickendantz and colleagues⁴ followed patients for >12 months, but the exact duration was not specified. In order to calculate the average duration of observation, each patient was assigned a duration of 12 months.

Of the 30 patients included in this review, 29 were treated conservatively. All of the included studies consisted of male patients. The mean age was 26.8 years (range 22 to 28.1 years). Of the 29 injuries treated conservatively, there were 2 LD tendon avulsions, 4 TM tendon avulsions, 1 LD and TM tendon avulsion, 7 LD intramuscular strains, 9 TM intramuscular strains, and 6 LD and TM intramuscular strains.

Treatment Protocol

The various treatment and rehabilitation programs used for the conservative patient population all followed a similar pathway. After initial injury, a rest period focused on stretching was implemented. Patients were started on steroid or anti-inflammatory medications, cryotherapy, or other therapeutic modalities. Once pain-free and full range of motion was achieved, patients began the strength and throwing components of the rehabilitation program. Reoccurrence of symptoms would halt the throwing component of the rehabilitation program until symptoms improved. Patients were progressed through a return-to-throw program and once they could throw off the mound and achieve their preinjury velocity, strength, and range of motion, they were cleared to return to competitive pitching.

In the senior author’s (MSS) practice, all throwers are managed with the same nonoperative protocol.⁴ Initial treatment consists of short periods of rest and symptom control via the application of cryotherapy, among other modalities. Restoration of preinjury range of motion is achieved with active-assisted stretching exercises. As range of motion begins approaching pre-injury levels, strength training is initiated with isometric strengthening of the LD and TM progressing to resistance exercises. Exercising the abdominal core, strengthening the lower body, and cardiovascular conditioning are focal points of the rehabilitation period. Once patients regain preinjury shoulder strength and range of motion without pain, they begin a throwing program that consists of 4 weeks of long toss followed by 2 weeks of throwing from the pitching mound. After completion of the throwing program, the patient is allowed to return to competitive pitching. For patients who did not suffer season-ending injury, the average time required to return to play was 99.8 days (range 72.3 to 182.6 days).

 

Complications and Reinjury

The patients in Leland and colleagues⁸ and Malcolm and colleagues⁷ did not suffer any complications or reinjuries. In Schickendantz and colleagues⁴, all but 3 of the 10 patients were able to return to full speed pitching by 3 months. The other 3 required 4, 6, and 10 months. The patient that required 10 months tore both his LD and TM and the patient that required 6 months tore his TM and was never able to regain his pre-injury throwing velocity. None of the TM tears had a recurrence, while 1 LD tear had a recurrence of injury 6 months after returning to competitive pitching. This patient was successfully treated with 6 weeks of conservative rest and rehabilitation.

In Nagda and colleagues⁹, 2 athletes suffered injury recurrence. One athlete with a LD strain suffered 2 subsequent LD strains, 4 months and 1 year after initial injury. The other athlete with a LD avulsion suffered a subsequent TM avulsion 13 months after initial injury. One pitcher who had an LD and TM strain suffered a superior labrum anterior and posterior (SLAP) tear and was never able to return to his prior level of play.

Surgical Treatment

Only 1 of the 5 included studies utilized surgical repair for their patient.¹⁰ The single patient suffered an avulsion injury of the distal LD tendon and its insertion on the humerus. The LD tendon was retracted approximately 5 cm from the distal humeral insertion. The TM was not involved. Eight days post-injury, the patient underwent surgical repair.¹¹ Postoperatively, the patient started passive range of motion after 2 weeks and active range of motion after 6 weeks. He started throwing at 12 weeks and returned to play at 30 weeks after he had returned to his preinjury form in regards to muscle strength, pitch control, and velocity. The patient was able to resume pitching at a high level in MLB.

Discussion

Overhand throwing athletes, especially professional baseball players, have to constantly deal with a variety of shoulder injuries.^12,13 Currently, there is minimal literature on isolated TM and LD injuries. As a result, there is still debate about the optimal treatment method for these injuries, especially in athletes who compete at the highest level. In order to treat isolated injuries of these muscles, it is important to understand their anatomic relationship, as these 2 muscles are intimately associated. The LD originates from the thoracolumbar spine and inserts on the proximal humerus between the pectoralis<hl name="2"/> major and TM tendons. The TM originates from the scapula and, similar to the LD, inserts on the proximal humerus. In an anatomic study, the TM tendon inserted into the LD tendon before its humeral insertion in the majority of cadavers.^14,15

The LD is responsible for extension, adduction, and internal rotation of the humerus. The TM, while not as extensively studied, is believed to also contribute to extension, adduction, and internal rotation of the humerus.¹⁶ As Jobe and colleagues⁵ demonstrated, the LD is vital during the acceleration phase of pitching. While they were unable to make any conclusions about the role of the TM during the pitching cycle, it is reasonable to hypothesize that these 2 muscles work together. While it is thought that these 2 muscles work as a unit, it is significant to note that a professional pitcher can sustain an isolated injury to the TM without injury to the LD, and vice versa. This questions whether these 2 muscles work more independently than once thought. One hypothesis is that the physical size of the LD provides protection from injuries that the smaller TM cannot overcome. This is a potential area of further research.

The most common findings in patients with TM injuries include swelling, bruising, tenderness of the proximal arm, and limitations of shoulder range of motion in abduction, flexion, and external rotation. There is also weakness when resistance is applied against internal rotation and extension. Similar to the TM, common findings in patients with LD injuries include pain in the posterior shoulder, bruising, and weakness when resistance is applied against internal rotation of the shoulder. Pitchers are often able to pinpoint the occurrence of their acute pain during a specific time in the game. They commonly experience a pulling sensation and sometimes even feel a “pop” in their shoulder followed by an acute onset of pain and stiffness in the posterior aspect of the axilla. These injuries seem to be associated with the pitcher throwing a “breaking ball,” a pitch that requires greater shoulder rotation since it changes trajectory while traveling towards home plate. Despite the clear role of the LD and hypothesized role of the TM in the pitching sequence, there has been limited research on the optimal treatment of isolated injuries of these muscles in MLB pitchers. The majority of studies in this review opted for conservative treatment for both LD and TM injuries. The only study that presented a surgical option was for a LD avulsion injury.

 

Athletes undergoing either conservative or surgical treatment required a significant period of recovery and rehabilitation before they were able to compete at the professional level. In Leland and colleagues⁸, it took about 10 to 12 weeks of rehabilitation for both pitchers to return to pitching against competition. In Schickendantz and colleagues⁴, barring any complications or injury recurrence, it took patients 12 weeks to return to their preinjury level. In Malcolm and colleagues⁷, magnetic resonance imaging after 8 weeks showed marked recovery, and shortly after the pitcher was able to return to the pitching rotation. In Nagda and colleagues⁹, the time lost to injury ranged from 7 weeks to an entire season. Of the 9 pitchers who were lost for the season, 6 had avulsion injuries. The other 3 consisted of an LD strain, TM strain, and LD plus TM strain.⁹ In this study, it seems that avulsion injuries had a more significant impact on patient recovery. On average, it took 35.6 days after injury for players to begin throwing. In contrast, it took an average of 65.5 days after an avulsion injury for players to begin throwing. Ellman and colleagues¹⁰ included the only surgically repaired injury, and it was for an avulsion of the LD tendon. In the surgical case, it took slightly longer for the pitcher to return to preinjury form. It took him 12 to 16 weeks to begin light throwing and his full return to pitching took about 20 to 30 weeks. Since muscle strains and tendon avulsions are significantly different injuries in regards to the type of soft tissue damage and healing potential, they may require different treatment strategies. An avulsion injury may require more aggressive intervention, whereas a strain may only require conservative rehabilitation. Ultimately, there does not seem to be a significant benefit of one treatment option compared to the other. The majority of conservatively managed pitchers were able to return to previous form in a reasonable time frame. While each rehabilitation protocol was slightly different, multiple studies advocated for rehab programs that centered around the following goals: slowly progressing pitchers to light throwing once their pain resolved, followed by long throwing, then throwing off of the mound, and finally returning to competitive pitching. It is important to discuss with patients that rehabilitation generally takes 12 to 16 weeks before they are able to fully return to pitching against competition and that rest should immediately follow any recurrence of pain or stiffness. Once those symptoms resolve, patients may continue the rehabilitation protocol.

As with any form of treatment, there are risks involved. This holds true for both conservative and nonconservative therapy for LD and TM injuries. One risk of nonoperative treatment of an LD avulsion is the development of strength deficits in the muscle.¹⁷ While this deficit may go unnoticed in a recreational athlete, it may be more pronounced in a professional athlete, especially since the LD of a professional baseball pitcher is more active on electromyography during the acceleration phase of the pitching cycle compared to a recreational athlete.¹⁸ Another risk of conservative treatment of an LD avulsion is jeopardizing the potential for future surgery. As a result, some advocate for early surgical intervention of an acute LD avulsion.^19,20 Others, however, recommend conservative management with subsequent surgical intervention if conservative measures fail. One caveat is that surgical intervention to restore the original anatomy may become difficult after a certain period of time due to the buildup of scar tissue. Surgical intervention also has associated risks, such as nerve injury, infection, vascular damage, persistent pain, and the buildup of large amounts of scar tissue. It is important to discuss these risks with patients when deciding on a treatment option.

LD and TM avulsion and tears typically present after an acute event in throwing athletes. There are a number of case reports published that demonstrate successful outcomes with both nonoperative management²¹ and operative repair of LD injuries in non-throwing athletes such as competitive water skiers,^22,23 steer wrestlers,²⁴ professional wrestlers,²⁵ and recreational rock climbers.²⁶ The 5 studies included in this review were the first ones to present LD and TM injuries in MLB pitchers. They discussed the outcomes of mainly conservative and surgical management of LD and TM avulsion and tears. Unfortunately, there remains a limited number of cases on the treatment of these injuries in highly competitive throwing athletes. Further research is required to elucidate the advantages and disadvantages of operative vs nonoperative treatment. The goal of this review is to provide clinicians with a concise summary of the current literature so that they may offer some evidence to their patients when discussing appropriate treatment plans.

Upper extremity injuries are very common in pitchers in amateur and professional baseball. The vast majority involving labral or rotator cuff pathology.^1-3 While uncommon, injuries to the latissimus dorsi (LD) (Figure) and teres major (TM) have been reported in Major League Baseball (MLB) pitchers.⁴ Jobe and colleagues⁵ demonstrated the role of the LD during the various phases of pitching. The LD is most active during the acceleration phase and remains active during the deceleration phase and follow-through.⁶ Anatomically, the TM lies posterior to the LD separated by bursal tissue. The tendon fibers converge and unite along their lower borders, leading to a synergistic mechanism of action.

Due to the rarity of LD and TM injuries, literature on the pathology and appropriate treatments for these injuries is limited. The goal of this review is to present the current literature on professional baseball players who have undergone either nonsurgical treatment or surgery for LD and TM strains and/or avulsion injuries. This review will ultimately assist clinicians when deciding on the optimal treatment method for professional baseball players.

Methods

We performed an extensive Medline database search with the following search algorithm: ([latissimus OR latissimus dorsi OR teres major] AND baseball). The search returned 20 citations. Inclusion criteria consisted of clinical studies that focused on professional baseball pitchers with TM and/or LD injuries that underwent either conservative nonsurgical treatment or surgical repair. There was no exclusion based on the type of injury present, such as avulsion vs strain. Any study with amateur athletes or athletes from other sports such as handball or rugby were excluded. Due to the limited amount of data available, the majority of included studies were case reports and case series.

Based on these parameters, 5 articles met criteria for inclusion. Of the 5 included studies, 3 were case reports and 2 were case series. From the eligible articles, the following information was obtained: publication year, sample size, mean age, mean follow-up duration, type of treatment (conservative vs surgical), ability to return to original level of play, time required to return to original form, and complications (Tables 1, 2).

Results

Nonoperative Management

Four of the 5 included studies implemented only conservative therapy for their patients.^4,7-9 The average duration these patients were followed for during treatment and rehabilitation was 26.3 months. Malcolm and colleagues⁷ followed patients for 8 months, the shortest length among the 4 conservative studies in this review. Leland and colleagues8 followed patients for 17 months, and Nagda and colleagues⁹ had the longest length of observation of 36 months (range 12 to 82 months).Schickendantz and colleagues⁴ followed patients for >12 months, but the exact duration was not specified. In order to calculate the average duration of observation, each patient was assigned a duration of 12 months.

Of the 30 patients included in this review, 29 were treated conservatively. All of the included studies consisted of male patients. The mean age was 26.8 years (range 22 to 28.1 years). Of the 29 injuries treated conservatively, there were 2 LD tendon avulsions, 4 TM tendon avulsions, 1 LD and TM tendon avulsion, 7 LD intramuscular strains, 9 TM intramuscular strains, and 6 LD and TM intramuscular strains.

Treatment Protocol

The various treatment and rehabilitation programs used for the conservative patient population all followed a similar pathway. After initial injury, a rest period focused on stretching was implemented. Patients were started on steroid or anti-inflammatory medications, cryotherapy, or other therapeutic modalities. Once pain-free and full range of motion was achieved, patients began the strength and throwing components of the rehabilitation program. Reoccurrence of symptoms would halt the throwing component of the rehabilitation program until symptoms improved. Patients were progressed through a return-to-throw program and once they could throw off the mound and achieve their preinjury velocity, strength, and range of motion, they were cleared to return to competitive pitching.

In the senior author’s (MSS) practice, all throwers are managed with the same nonoperative protocol.⁴ Initial treatment consists of short periods of rest and symptom control via the application of cryotherapy, among other modalities. Restoration of preinjury range of motion is achieved with active-assisted stretching exercises. As range of motion begins approaching pre-injury levels, strength training is initiated with isometric strengthening of the LD and TM progressing to resistance exercises. Exercising the abdominal core, strengthening the lower body, and cardiovascular conditioning are focal points of the rehabilitation period. Once patients regain preinjury shoulder strength and range of motion without pain, they begin a throwing program that consists of 4 weeks of long toss followed by 2 weeks of throwing from the pitching mound. After completion of the throwing program, the patient is allowed to return to competitive pitching. For patients who did not suffer season-ending injury, the average time required to return to play was 99.8 days (range 72.3 to 182.6 days).

 

Complications and Reinjury

The patients in Leland and colleagues⁸ and Malcolm and colleagues⁷ did not suffer any complications or reinjuries. In Schickendantz and colleagues⁴, all but 3 of the 10 patients were able to return to full speed pitching by 3 months. The other 3 required 4, 6, and 10 months. The patient that required 10 months tore both his LD and TM and the patient that required 6 months tore his TM and was never able to regain his pre-injury throwing velocity. None of the TM tears had a recurrence, while 1 LD tear had a recurrence of injury 6 months after returning to competitive pitching. This patient was successfully treated with 6 weeks of conservative rest and rehabilitation.

In Nagda and colleagues⁹, 2 athletes suffered injury recurrence. One athlete with a LD strain suffered 2 subsequent LD strains, 4 months and 1 year after initial injury. The other athlete with a LD avulsion suffered a subsequent TM avulsion 13 months after initial injury. One pitcher who had an LD and TM strain suffered a superior labrum anterior and posterior (SLAP) tear and was never able to return to his prior level of play.

Surgical Treatment

Only 1 of the 5 included studies utilized surgical repair for their patient.¹⁰ The single patient suffered an avulsion injury of the distal LD tendon and its insertion on the humerus. The LD tendon was retracted approximately 5 cm from the distal humeral insertion. The TM was not involved. Eight days post-injury, the patient underwent surgical repair.¹¹ Postoperatively, the patient started passive range of motion after 2 weeks and active range of motion after 6 weeks. He started throwing at 12 weeks and returned to play at 30 weeks after he had returned to his preinjury form in regards to muscle strength, pitch control, and velocity. The patient was able to resume pitching at a high level in MLB.

Discussion

Overhand throwing athletes, especially professional baseball players, have to constantly deal with a variety of shoulder injuries.^12,13 Currently, there is minimal literature on isolated TM and LD injuries. As a result, there is still debate about the optimal treatment method for these injuries, especially in athletes who compete at the highest level. In order to treat isolated injuries of these muscles, it is important to understand their anatomic relationship, as these 2 muscles are intimately associated. The LD originates from the thoracolumbar spine and inserts on the proximal humerus between the pectoralis<hl name="2"/> major and TM tendons. The TM originates from the scapula and, similar to the LD, inserts on the proximal humerus. In an anatomic study, the TM tendon inserted into the LD tendon before its humeral insertion in the majority of cadavers.^14,15

The LD is responsible for extension, adduction, and internal rotation of the humerus. The TM, while not as extensively studied, is believed to also contribute to extension, adduction, and internal rotation of the humerus.¹⁶ As Jobe and colleagues⁵ demonstrated, the LD is vital during the acceleration phase of pitching. While they were unable to make any conclusions about the role of the TM during the pitching cycle, it is reasonable to hypothesize that these 2 muscles work together. While it is thought that these 2 muscles work as a unit, it is significant to note that a professional pitcher can sustain an isolated injury to the TM without injury to the LD, and vice versa. This questions whether these 2 muscles work more independently than once thought. One hypothesis is that the physical size of the LD provides protection from injuries that the smaller TM cannot overcome. This is a potential area of further research.

The most common findings in patients with TM injuries include swelling, bruising, tenderness of the proximal arm, and limitations of shoulder range of motion in abduction, flexion, and external rotation. There is also weakness when resistance is applied against internal rotation and extension. Similar to the TM, common findings in patients with LD injuries include pain in the posterior shoulder, bruising, and weakness when resistance is applied against internal rotation of the shoulder. Pitchers are often able to pinpoint the occurrence of their acute pain during a specific time in the game. They commonly experience a pulling sensation and sometimes even feel a “pop” in their shoulder followed by an acute onset of pain and stiffness in the posterior aspect of the axilla. These injuries seem to be associated with the pitcher throwing a “breaking ball,” a pitch that requires greater shoulder rotation since it changes trajectory while traveling towards home plate. Despite the clear role of the LD and hypothesized role of the TM in the pitching sequence, there has been limited research on the optimal treatment of isolated injuries of these muscles in MLB pitchers. The majority of studies in this review opted for conservative treatment for both LD and TM injuries. The only study that presented a surgical option was for a LD avulsion injury.

 

Athletes undergoing either conservative or surgical treatment required a significant period of recovery and rehabilitation before they were able to compete at the professional level. In Leland and colleagues⁸, it took about 10 to 12 weeks of rehabilitation for both pitchers to return to pitching against competition. In Schickendantz and colleagues⁴, barring any complications or injury recurrence, it took patients 12 weeks to return to their preinjury level. In Malcolm and colleagues⁷, magnetic resonance imaging after 8 weeks showed marked recovery, and shortly after the pitcher was able to return to the pitching rotation. In Nagda and colleagues⁹, the time lost to injury ranged from 7 weeks to an entire season. Of the 9 pitchers who were lost for the season, 6 had avulsion injuries. The other 3 consisted of an LD strain, TM strain, and LD plus TM strain.⁹ In this study, it seems that avulsion injuries had a more significant impact on patient recovery. On average, it took 35.6 days after injury for players to begin throwing. In contrast, it took an average of 65.5 days after an avulsion injury for players to begin throwing. Ellman and colleagues¹⁰ included the only surgically repaired injury, and it was for an avulsion of the LD tendon. In the surgical case, it took slightly longer for the pitcher to return to preinjury form. It took him 12 to 16 weeks to begin light throwing and his full return to pitching took about 20 to 30 weeks. Since muscle strains and tendon avulsions are significantly different injuries in regards to the type of soft tissue damage and healing potential, they may require different treatment strategies. An avulsion injury may require more aggressive intervention, whereas a strain may only require conservative rehabilitation. Ultimately, there does not seem to be a significant benefit of one treatment option compared to the other. The majority of conservatively managed pitchers were able to return to previous form in a reasonable time frame. While each rehabilitation protocol was slightly different, multiple studies advocated for rehab programs that centered around the following goals: slowly progressing pitchers to light throwing once their pain resolved, followed by long throwing, then throwing off of the mound, and finally returning to competitive pitching. It is important to discuss with patients that rehabilitation generally takes 12 to 16 weeks before they are able to fully return to pitching against competition and that rest should immediately follow any recurrence of pain or stiffness. Once those symptoms resolve, patients may continue the rehabilitation protocol.

As with any form of treatment, there are risks involved. This holds true for both conservative and nonconservative therapy for LD and TM injuries. One risk of nonoperative treatment of an LD avulsion is the development of strength deficits in the muscle.¹⁷ While this deficit may go unnoticed in a recreational athlete, it may be more pronounced in a professional athlete, especially since the LD of a professional baseball pitcher is more active on electromyography during the acceleration phase of the pitching cycle compared to a recreational athlete.¹⁸ Another risk of conservative treatment of an LD avulsion is jeopardizing the potential for future surgery. As a result, some advocate for early surgical intervention of an acute LD avulsion.^19,20 Others, however, recommend conservative management with subsequent surgical intervention if conservative measures fail. One caveat is that surgical intervention to restore the original anatomy may become difficult after a certain period of time due to the buildup of scar tissue. Surgical intervention also has associated risks, such as nerve injury, infection, vascular damage, persistent pain, and the buildup of large amounts of scar tissue. It is important to discuss these risks with patients when deciding on a treatment option.

LD and TM avulsion and tears typically present after an acute event in throwing athletes. There are a number of case reports published that demonstrate successful outcomes with both nonoperative management²¹ and operative repair of LD injuries in non-throwing athletes such as competitive water skiers,^22,23 steer wrestlers,²⁴ professional wrestlers,²⁵ and recreational rock climbers.²⁶ The 5 studies included in this review were the first ones to present LD and TM injuries in MLB pitchers. They discussed the outcomes of mainly conservative and surgical management of LD and TM avulsion and tears. Unfortunately, there remains a limited number of cases on the treatment of these injuries in highly competitive throwing athletes. Further research is required to elucidate the advantages and disadvantages of operative vs nonoperative treatment. The goal of this review is to provide clinicians with a concise summary of the current literature so that they may offer some evidence to their patients when discussing appropriate treatment plans.