THERAPEUTIC HYPOTHERMIA AND TEMPERATURE MANAGEMENT Volume 3, Number 4, 2013 ª Mary Ann Liebert, Inc. DOI: 10.1089/ther.2013.0015
Urine Output Changes During Postcardiac Arrest Therapeutic Hypothermia Jaron D. Raper1 and Henry E. Wang 2
While commonly described, no studies have characterized cold-induced diuresis or rewarm anti-diuresis occurring during the delivery of therapeutic hypothermia (TH). We sought to determine urine output changes during the provision of postcardiac arrest TH. We analyzed clinical data on patients receiving postcardiac arrest TH at an urban tertiary care center. TH measures included cooling by cold intravenous fluid, external ice packs, and a commercial external temperature management system. TH treatment was divided into phases: (1) induction, (2) maintenance, (3) rewarm, and (4) post-rewarm. The primary outcome measure was the mean urine output rate (mL/hour). We compared urine output rates between TH phases using a Generalized Estimating Equations model, defining urine output rate (mL/hour) as the dependent variable and TH phase (induction, maintenance, rewarm, and post-rewarm) as the primary exposure variable. We adjusted for age, sex, initial ECG rhythm, location of arrest, shock, acute kidney injury, rate of intravenous fluid input, and body mass index. Complete urine output data were available on 33 patients. Mean urine output rates during induction, maintenance, rewarm, and post-rewarm phases were 157 mL/hour (95% CI: 104–210), 103 mL/hour (95% CI: 82–125), 70 mL/hour (95% CI: 51–88), and 91 mL/hour (95% CI: 65–117), respectively. Compared with the post-rewarm phase, adjusted urine output was higher during the TH induction phase (output rate difference + 51 mL/hour; 95% CI: 3–99). Adjusted urine output during the maintenance and rewarm phases did not differ from the postrewarm phase. In this preliminary study, we observed modest increases in urine output during TH induction. We did not observe urine output changes during TH maintenance or rewarming.
herapeutic hypothermia (TH) is a recommended treatment for comatose initial survivors of cardiac arrest (Nolan et al., 2003). TH has many hypothesized effects, including the reduction of cerebral metabolism, prevention of reperfusion injury, and the inhibition of destructive cellular processes such as apoptosis, mitochondrial dysfunction, excitotoxicity, inflammation, and free radical production, among others (Polderman, 2009). Clinical guidelines suggest that TH increases the urine output through the induction of cold-induced diuresis (Polderman, 2009). While not precisely defined, animal models point to decreases in the anti-diuretic hormone (ADH) as a potential physiologic mechanism for cold-induced diuresis (Broman et al., 1998). In addition, these studies suggest that ADH-mediated anti-diuresis (with corresponding decreases in urine output) occurs during rewarming (Broman et al., 1998; Polderman, 2009). Although commonly highlighted, only limited human data support the phenomena of cold-
induced diuresis and rewarm anti-diuresis. In addition, many confounding factors may influence urine output in these patients. For example, post-arrest patients often receive resuscitation fluids, and the presence of cardiogenic shock or acute kidney injury (AKI) could influence urine production. An understanding of TH-associated effects on urine production is important because post-arrest patients often have hemodynamic instability, requiring fluid resuscitation and titration of vasopressors (Peberdy et al., 2010). In addition, electrolyte losses and accumulation may be important as many of these patients suffer from or are susceptible to cardiac dysrhythmias (Vanden Hoek et al., 2010). In this study, we sought to characterize urine output changes during the provision of post-cardiac arrest TH. Materials and Methods Study design We performed a secondary analysis of prospectively collected data on patients receiving postcardiac arrest TH at an
University of Alabama School of Medicine, Birmingham, Alabama. Department of Emergency Medicine, University of Alabama School of Medicine, Birmingham, Alabama. Presented at: Society for Critical Care Medicine Annual Congress, January 2013, Puerto Rico. 2
174 urban tertiary care center. The study was approved by the Institutional Review Board of the University of Alabama at Birmingham (UAB). Study setting UAB Hospital is an urban academic tertiary care referral medical center located in Birmingham, AL. The 908-bed institution contains a 64,000 visit per year emergency department, is the only Level I trauma center in Alabama, and has eight intensive care units containing more than 180 critical care beds. The hospital has provided postcardiac arrest TH since 2009 (Wang et al., 2011). TH protocols include all cardiac arrest patients with return of spontaneous circulation and persistent coma. The TH protocol includes cardiac arrests occurring in the out-of-hospital, Emergency Department as well as select inhospital settings. The TH protocol includes cardiac arrests of all initial electrocardiographic rhythms. Methods for TH include ice-cold intravenous saline, external ice pillows, and a commercial water-circulating temperature management system (Arctic Sun, Inc.; Bard Medical, Inc., Covington, GA). The TH protocol specifies cooling of patients rapidly to 33C, maintenance of hypothermia for 24 hours, and then a slow rewarm at 0.25–0.5C/hour. Selection of adjunctive sedatives, analgesics, and neuromuscular blocking agents are per physician discretion. All TH efforts are coordinated by a physician response team. Selection of participants We included adult (q18 years) initial survivors from the out-of-hospital, Emergency Department or in-hospital cardiac arrest receiving TH efforts. We limited the analysis to patients who completed the entire TH protocol, including TH induction, 24 hours of TH maintenance, rewarm, and 12 hours of post-rewarm maintenance of normothermia. We excluded patients with end stage renal disease, those who received inpatient hemodialysis, and those who did not reach the goal temperature of 33C. Data collection The TH program maintains an electronic registry (Microsoft Access, Microsoft, Inc., Redmond, WA) of all patients undergoing TH, including information on patient demographics, initial presentation, methods of cooling, complications, and outcomes. For this analysis, we supplemented TH registry data with information from the patient medical record, which included both paper (for example, Emergency Department critical care records) and electronic elements (Cerner Millennium; Cerner, Inc., Kansas City, MT). A medical record review was accomplished by the lead investigator with random quality checks by the senior investigator. Outcomes and covariates The primary outcome measure was the urine output rate, defined as milliliters of urine output per hour. All patients undergoing TH underwent urinary catheterization. We determined the urine output rate from a review of the Emergency Department and intensive care unit fluid input/output records. We did not include urine output from nonurinary sources such as gastric output. If complete urine output records were not available, we excluded the case from the analysis.
RAPER AND WANG We identified the urine output rate for four phases of TH treatment: (1) induction, (2) maintenance, (3) rewarm, and (4) post-rewarm normothermia maintenance. TH induction encompassed the period from initiation of TH to attainment of goal temperature (T = 33C) and typically ranged from 1 to 4 hours. Target TH maintenance duration was 24 hours. Rewarm occurred at a rate of 0.25–0.5C/hour and typically lasted for 8–16 hours. Whereas the post-rewarm normothermia maintenance phase may last for several days, in this study, we examined the first 12 hours only. We determined the mean urine output rate by averaging the hourly urine output rate for each phase. We identified other clinical data with plausible impact upon the urine output rate, including patient age, sex, body mass index, location of arrest, initial electrocardiographic rhythm, hypotension, AKI, and intravenous fluid input rate. We defined hypotension as the initiation of vasopressors. We determined intravenous fluid input rates from the review of Emergency Department and intensive care unit medication administration records. We did not include out-of-hospital fluids in the model because Emergency Medical Service practitioners in our community do not report fluid input volumes for cardiac arrest patients. Previous studies describe AKI in 12–28.6% of postarrests (Mattana and Singhal, 1993; Domanovits et al., 2001). Because it may influence urine output, we adjusted for AKI in the analysis. We identified AKI by examining all serum creatinine values collected during the first 48 hours of hospitalization. Based upon the AKI network criteria, we defined AKI as an increase in serum creatinine of q0.3 mg/dL from initial creatinine during the first 48 hours (Mehta et al., 2007). Data analysis We calculated the hourly intravenous fluid input and urine output rates for each TH phase (induction, maintenance, rewarm, and post-rewarm). For example, for the induction phase, we divided total infused intravenous fluids by the number of TH induction hours. For analytic purposes, we defined post-rewarm as the reference category, calculating differences in urine output rates relative to this phase. We chose the post-rewarm phase as the reference category because it was not possible to determine a patient’s baseline urine output before the onset of cardiac arrest. Of the data available, the post-rewarm period reflected the best available approximation of baseline urine output. We compared urine output rates between TH phases by fitting a Generalized Estimating Equations (GEE) model, defining urine output rate (mL/hour) as the outcome variable and TH phase (induction, maintenance, rewarm, postrewarm) as the primary exposure variable (Hardin and Hilbe, 2003). To account for potential confounders, we fit a second regression model, adjusting for age, sex, initial ECG rhythm, location of arrest, hypotension, AKI, and rate of intravenous fluid input. Because obesity may impact the fluid balance, we also fit a model incorporating body mass index as an additional covariate. We performed all analyses using Stata 12.2 (Stata, Inc., College Station, TX). Results Of 179 patients receiving TH, we excluded 114 patients who did not have complete urine output records, 10 patients
URINE OUTPUT AND HYPOTHERMIA
Table 1. Patient Characteristics Characteristic
7 (21) 15 (45)
patients suffered out-of-hospital arrests. Few experienced shock, and just over half had AKI. Approximately half survived to hospital discharge. There was no association between AKI and hospital survival (chi-square p = 0.9). Mean duration of each TH treatment phase was induction 4.8 hours, maintenance 22.6 hours, and rewarm 11.1 hours (Table 2). For this analysis, we limited the post-rewarm phase to 12 hours. Mean urine output rates were induction 159 mL/ hour, maintenance 96 mL/hour, rewarm 68 mL/hour, and post-rewarm maintenance 91 mL/hour (Table 2). Compared with the post-rewarm phase, urine output was higher for the induction phase (Table 2). Urine output rates were similar between the maintenance and post-rewarm, and between the rewarm and post-rewarm phases. The increased induction urine output rate persisted after adjustment for fluid input rate, age, sex, hypotension, arrest location, initial arrest rhythm, and AKI at 48 hours. Body mass index was not available for two patients. The increased urine output rate persisted after additional adjustment for body mass index. Urine output rates for the maintenance and rewarm phases remained similar to the post-rewarm phase, even after adjustment for confounders.
15 (45) 18 (55)
Age (mean – SD) Sex Female Male Body mass index (mean – SD)a Arrest location Emergency department In-hospital Out-of-hospital Initial arrest rhythm Asystole Pulseless electrical activity Ventricular fibrillation Ventricular tachycardia Hypotension Acute kidney injury At 24 hours At 48 hours Hospital survival Alive Dead
57.0 – 15.7 11 (33) 22 (67) 31.2 – 8.7 5 (15) 7 (21) 21 (64) 3 12 14 4 2
(9) (36) (42) (12) (6)
Includes 33 patients with complete fluid input and output records. a Body mass index not available for two patients.
suffering from end stage renal disease, 17 patients who received hemodialysis, 3 patients who were < 18 years of age, and 2 patients who did not reach goal temperature. We included 33 patients with complete fluid input and output data in the final analysis. BMI data were complete for 31 of the 33 included patients. The patient population was mostly male, older, and obese (BMI > 30 kg/m2) (Table 1). Two-thirds of the
Compared with the TH post-rewarm period, we observed a modest increase in urine output rates during TH induction. This effect persisted even after adjustment for numerous clinical confounders, including intravenous fluid input, shock, AKI, and body mass index. However, we did not detect any evidence of urine output increases or decreases during the TH maintenance or rewarm phases. Whereas our results are preliminary in nature and based upon a limited series, the findings support the potential presence of cold-induced dieresis, but not rewarm anti-diuresis during TH delivery.
Table 2. Fluid Input and Output During Therapeutic Hypothermia Therapeutic hypothermia treatment phase Hypothermia induction Duration (mean, hours, 95% CI) Intravenous fluid input Total fluid input (mean, mL, 95% CI) Fluid input rate (mean, mL/hour, 95% CI) Urine output Total urine output (mean, mL, 95% CI) Urine output rate (mean, mL/hour, 95% CI) Difference in urine output rate relative to post-rewarm phase (mean, mL/hour, 95% CI)—unadjusted Difference in urine output rate relative to post-rewarm phase (mean, mL/hour, 95% CI)—adjustedb Difference in urine output rate relative to post-rewarm phase (mean, mL/hour, 95% CI)—adjustedc
2323 (1710–2937) 546 (367–725)
3245 (2395–4094) 141 (102–180)
1448 (1030–1865) 129 (97–161)
1306 (978–1635) 109 (81–136)
724 (442–1006) 157 (104–210) 65 (24–107) p = 0.002a
2476 (1931–3021) 103 (82–125) 12 ( - 29–54) p = 0.57
770 (545–994) 70 (51–88) - 21 ( - 63–20) p = 0.31
1095 (784–1405) 91 (65–117) Referent
51 (3–99) p = 0.04a
11 ( - 30–52) p = 0.60
- 22 ( - 63–19) p = 0.29
57 (7–107) p = 0.03a
13 ( - 30–56) p = 0.56
- 23 ( - 67–20) p = 0.29
Includes n = 33 patients with complete fluid input and output records. Differences in urine output rates determined from a Generalized Estimating Equations model. a Statistically significant at p < 0.05. b Adjusted for fluid input rate, age, sex, hypotension, arrest location, initial arrest rhythm, and acute kidney injury at 48 hours. c Adjusted for fluid input rate, age, sex, hypotension, arrest location, initial arrest rhythm, acute kidney injury at 48 hours and body mass index.
RAPER AND WANG
Guluma et al. (2010) evaluated urine output in conscious stroke patients undergoing TH, but found a 5.1-mL/hour decrease in urine output per 1C decrease in body temperature that persisted during hypothermia maintenance. There are important differences between the Guluma et al. and our study. We studied postcardiac arrest patients; compared with stroke patients, these individuals often have systemic complications such as shock, cerebral edema, and AKI. In addition, postcardiac arrest syndrome involves body-wide ischemia involving all organ systems, whereas stroke involves the brain. Using a GEE model, we were able to account for several confounders not examined in the Guluma analysis, such as age, sex, hypotension, and BMI. The patients in our series also received significant volumes of intravenous fluid (on the order of > 500 mL/hour during TH induction). Whereas stroke management practices vary, intravenous fluid administration is not usually a priority. The contrasting results of these studies highlight that, while the principles of TH may be similar between different disease states, the physiologic responses may be very different. The results of this study clearly merit replication with a larger series. However, if independently validated, the findings would indicate that clinicians may titrate postarrest fluid resuscitation and vasopressor therapy without significant adjustment for TH-associated urine output changes. The slight increase in cold diuresis observed in this series (on the order of 50 mL/hour) would translate to *1 L of excess fluid loss over a 24-hour period. This quantity is relatively modest compared with the large volumes of fluid often required in the setting of shock.
measured every 6 hours on TH patients. However, potassium and magnesium levels are potentially influenced by a wide range of confounders, including the varying timing and quantity of electrolyte replacement and the administration of diuretics. The assessment of electrolyte trends is analytically complex and beyond the scope of this study. We adjusted for the confounding influence of AKI upon urine output, defining AKI based upon serial creatinine measurements. However, Zeiner et al. (2004) found that TH may be associated with decreased creatinine clearance, without corresponding changes in serum creatinine. Therefore, our approach may not fully capture the extent of renal impairment in this population. However, multiple factors may influence kidney function in the critically ill. Our objective was to characterize urine output during TH—not to define TH-associated changes in renal function.
This study clearly has limitations. Our series was modestly sized. However, given the absence of any previous studies describing fluid shifts during TH, our study provides important preliminary insights, highlighting potential methodological approaches and illuminating directions for future studies. Whereas a myriad of factors may influence urinary output (for example, volume status, preload, cardiac output, baseline renal function, fluid administered, and the use of diuretics of pressors), many of these factors cannot be easily quantified in the setting of the postarrest patient. An important feature of our study was the illustration of GEE use to account for fluid shifts over time, while allowing for multivariable adjustments for many pertinent confounders such as AKI and body mass index. Future efforts to evaluate TH fluid shifts may potentially build upon this analytic strategy. We were able to include only a portion of our total TH cases due to the incomplete reporting of urine output. Of note, urine output reports were often missing from the Emergency Department, the most common site of TH induction at our institution. We similarly were not able to quantify fluids given by the Emergency Medical Services before hospital arrival. Urine output measurements are not common practice in either the out-of-hospital or Emergency Department setting. Future efforts must seek to better quantify urine output in these arenas. Another limitation was the absence of data on electrolyte shifts (particularly potassium and magnesium), which are potentially important even in the absence of significant fluid shifts. At our institution, electrolyte levels are routinely
All authors declare that no competing financial interests exist.
Conclusion In this preliminary study, we observed modest increases in urine output during TH induction. We did not observe urine output changes during TH maintenance or rewarming. Acknowledgments This project was supported by U01-HL077881 from the National Heart Lung and Blood Institute, P30-DK079337 from the National Institute of Diabetes and Digestive and Kidney Diseases, and the UAB/UCSD O’Brien Acute Kidney Injury Center Summer Research Program.
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Address correspondence to: Henry E. Wang, MD, MS Department of Emergency Medicine University of Alabama at Birmingham 619 19th St. South, OHB 251 Birmingham, AL 35249 E-mail: [email protected]