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Incidence and characterization of acute kidney injury after acetaminophen overdose
Journal of Critical Care 35 (2016) 191–194
Contents lists available at ScienceDirect
Journal of Critical Care journal homepage: www.jccjournal.org
Incidence and characterization of acute kidney injury after acetaminophen overdose Joanna L. Stollings, PharmD, FCCM, BCPS, BCCCP a,⁎, Arthur P. Wheeler, MD b,1, Todd W. Rice, MD, MSc b a b
Department of Pharmaceutical Services, Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN 37232, USA Division of Allergy/Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, 1211 Medical Center Drive, Nashville, TN 37232, USA
a r t i c l e
i n f o
a b s t r a c t
Keywords: Acetaminophen Acetylcysteine Acute renal failure Overdose Creatinine
Purpose: Acute kidney injury (AKI) occurs in 2–10% of patients with acetaminophen (APAP) overdose. Elevation in creatinine (SCr) typically occurs 2 to 5 days after ingestion, with a mean peak on day 7, and normalization over a month. However, it remains unclear whether renal impairment occurs without hepatotoxicity. We hypothesized that APAP-associated acute renal failure occurs in patients with and without severe liver dysfunction after APAP overdose. Materials and methods: We retrospectively evaluated all patients admitted to the Medical Intensive Care Unit at a tertiary hospital and received acetylcysteine between June 2009 and December 2014. Of the 303 patients meeting these criteria, 139 of these patients received acetylcysteine for APAP overdose. Of these patients, 138 had Model for End-Stage Liver Disease (MELD) Scores on Day 1 of admission. Using a modified MELD (m-MELD) score, only containing total bilirubin and international normalized ratio not the SCr, the median m-MELD score was calculated. Patients with m-MELD scores below the median were compared to those with scores above the median (low m-MELD score b2.9 or high m-MELD score N2.9). Results: Baseline demographics were similar in the two groups with the exception of more hypertension in the low m-MELD group (24 vs 7%; P= .02). Time to admission was shorter in the low m-MELD group (7.9 ± 9.3 vs. 25.7 ± 29.2 hours; P= .001). The mean admission APAP level was 96.9 (±119) μg/mL in the low compared to 52.3 (±85.3) μg/mL in the high m-MELD group (P= .012). Day one SCr (1.2 ± 0.9 vs 2.7 ± 2.2 mg/dL; Pb .0001) and change from baseline to highest SCr (0.2 ± 0.3 vs. 2.7 ± 3.3 mg/dL; Pb .0001) were both lower in the low m-MELD group compared to the high m-MELD group. In addition, renal failure resolved upon discharge in all 2 patients (3%) with AKI in the low m-MELD group as compared to only 19 patients (44%) in the high mMELD group. Conclusions: Mean day one SCr, maximum change in SCr, and lack of renal failure resolution were higher in patients with higher m-MELD scores. However, patients with low m-MELD scores presented much earlier than patients with high m-MELD scores and 26% developed AKI. © 2016 Elsevier Inc. All rights reserved.
1. Background
Failure Study Group were due to APAP toxicity making APAP the number one cause of liver failure in the United States [1]. APAP induced liver failure has been extensively studied [3]. However, extrahepatic effects of APAP overdoses such as acute kidney injury (AKI) are not widely discussed in the literature. AKI occurs in 2% to 10% of patients after APAP overdose [4]. However, one study reported that 79% of patients admitted to a tertiary referral liver intensive therapy unit developed AKI after APAP overdose [5]. Elevation in creatinine (SCr) typically occurs 2 to 5 days after ingestion, with a mean peak on day 7, and normalization over a month [4]. The proposed mechanism for APAP induced renal tubular damage is through the toxic metabolite N-acetyl-pbenzoquinoone-imine (NAPQI), produced via APAP metabolism by cytochrome P-450 isoenzymes present in the kidney. At therapeutic doses, less than 5% of APAP is metabolized to NAPQI. However, after
In 2005, more than 28 billion doses of acetaminophen (APAP) containing products were dispensed [1]. The American Association of Poison Control Center's National Poison Data System reported 400 deaths in 2013 secondary to APAP or an APAP combination product [2]. Nearly half of the cases of acute liver failure in the United States Acute Liver
⁎ Corresponding author at: 1211 Medical Center Drive, BUH-131, Nashville, TN, 37232. Tel.: +1 615 343 5376. E-mail addresses: [email protected] (J.L. Stollings), [email protected] (A.P. Wheeler), [email protected] (T.W. Rice). 1 Posthumous. http://dx.doi.org/10.1016/j.jcrc.2016.06.004 0883-9441/© 2016 Elsevier Inc. All rights reserved.
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overdose, glutathione depletion results in the generation of more NAPQI reactive intermediates [4]. Although 2 case reports have demonstrated renal impairment without evidence of hepatotoxicity [6,7], systematic evaluation of risk factors for AKI with APAP overdose are lacking. This retrospective review was performed to determine if AKI associated with APAP overdose is more frequently associated with severe liver dysfunction. 2. Methods All patients admitted to the Medical Intensive Care Unit (MICU) of a large, tertiary care academic medical center who received acetylcysteine between June 2009 and December 2014 were identified through a retrospective medication review. Patients were included if they received acetylcysteine for APAP overdose and had a Measure of End Stage Liver Disease (MELD) Score recorded on day 1 of admission. Using a modified MELD (m-MELD) score, only containing total bilirubin and international normalized ratio (INR), not the SCr, the median mMELD score was calculated. Patients were divided into 2 groups (low m-MELD Group [m-MELD b2.9] and high m-MELD Group [m-MELD ≥2.9]). Patients with baseline renal dysfunction were not excluded. The Vanderbilt University Institutional Review Board approved this study with waiver of informed consent. 2.1. Study objective The primary objective was to determine if AKI was associated with higher severity of liver dysfunction. 2.2. Definitions Nephrotoxins were defined as methotrexate, cyclosporine, tacrolimus, or nonsteroidal anti-inflammatory drugs. Inducers were defined as carbamazepine, phenytoin, phenobarbital, primidone, rifampin, and sulfonylureas. AKI was defined as SCr greater than 1.5 times baseline or an increase in SCr by 0.3 mg/dL in a 48-hour period. Baseline SCr was defined as the SCr before the admission for APAP overdose. Acute overdose was defined as an ingestion of an amount greater than the maximum recommended daily dose of APAP within a 24-hour period. Chronic overdose was defined as ingestion of an amount greater than the maximum recommended daily dose of APAP for a period of time greater than a 24-hour period. Hypoglycemia was defined as a glucose value of ≤60 mg/dL. Peak SCr was defined as the highest SCr value during the patient's hospitalization. Delta SCr was defined as the change from baseline to peak SCr. Resolution of renal failure was defined as no continuation of dialysis and a SCr clearance greater than 60 mL/min [8,9]. 2.3. Data collection Baseline data collected from the medical record included demographics, past medical history, and Acute Physiology and Chronic Health Evaluation (APACHE) II score. The following data were collected with regard to APAP: time to hospital admission, type of overdose, APAP levels and acetylcysteine administration. Measures of SCr, requirement of new dialysis, development and resolution of AKI, liver function tests, mental status assessments, determinants of coagulopathy, and outcome were collected. 2.4. Statistical analysis Categorical data are reported as numbers and percentages and analyzed using χ 2 test. Continuous data are reported as means ± SD and analyzed using Student t tests. A logistic regression was performed to assess whether variables were associated with the development of AKI. A linear regression was performed to assess whether variables
were associated with the change in SCr. Variables were chosen to be placed in the regressions based off statistical significance and primary features seen with acute liver failure while ensuring not to include colinear variables such as SCr or the individual components of the mMELD. Statistical analyses were performed with SPSS Version 23 (IBM, Inc, Armonk, NY). 3. Results Acetylcysteine was administered to 303 patients admitted to the MICU between June 2009 and December 2014. Of these, 139 received acetylcysteine for APAP overdose and 138 had MELD scores calculated on day 1. 3.1. Baseline demographics and admission diagnosis The median baseline m-MELD score was 2.9 (IQR, 1.7-7.5). There was no difference in baseline demographics between the low and high mMELD groups except in hypertension (Table 1). Admission to the outside hospital (7.9 ± 9.3 vs 25.7 ± 29.2 hours, P= .001) and to Vanderbilt University Medical Center (VUMC) (11.4 ± 14.6 vs 40.4 ± 30.6 hours, Pb .0001) both occurred earlier in the low m-MELD as compared to the high m-MELD group. The low m-MELD group had more acute overdoses as compared to the high m-MELD group (63 [93%] vs 52 [76%], P= .01), although the amount of APAP ingested and the initial APAP level did not differ significantly between groups. Time until the first APAP level (8.4 ± 8.2 vs 35.1 ± 30.6 hours, P≤ .0001) and time between ingestion and acetylcysteine administration (12.6 ± 11.1 vs 35.4 ± 23.9 hours, Pb .0001) were lower in the low m-MELD group (Table 1). AKI occurred in 8 patients (26%) with an initial m-MELD score below 2.9 as compared to 46 (69%) in the high m-MELD group, Pb .0001 (Table 3). Baseline SCr was 0.8 ± 0.2 mg/dL in the low as compared to 1.0 ± 0.9 mg/dL in the high m-MELD group, P= .26 (Table 1). Day 1 SCr (1.2 ± 0.9 vs. 2.7 ± 2.2 mg/dL; Pb .0001) and peak SCr (1.4 ± 1.3 vs. 3.3 ± 2.8 mg/dL; Pb .0001) were both lower in the low m-MELD
Table 1 Baseline demographics Characteristics
Low m-MELD (b2.9) (N = 68)
High m-MELD (≥2.9) (N = 70)
P
Age Sex (female) Race (white) APACHE II Score Past medical history Diabetes mellitus Chronic kidney disease Hypertension Chronic Alcohol Ingestion Acute APAP ingestion Nephrotoxins⁎ Inducers⁎⁎
41.9 ± 14.4 37 (54%) 61 (89%) 12.6 ± 8
39.1 ± 13.9 48 (70%) 64 (91%) 11.3 ± 8.4
.39 .06 .35 .36
7 (10%) 0 (0%) 16 (24%) 9 (13.2%) 63 (93%) 6 (9%) 2 (3%) 21.3 ± 18.2 7.9 ± 9.3 11.4 ± 14.6
2 (3%) 1 (1%) 5 (7%) 16 (23%) 52 (76%) 2 (3%) 0 (0%) 22.9 ± 32.5 25.7 ± 29.2 40.4 ± 30.6
.08 .32 .02 .14 .01 .13 .15 .85 .001 b.0001
1st APAP Level (μg/mL) Time Until 1st APAP Level (h)
96.9 ± 119 8.4 ± 8.2
52.3 ± 85.3 35.1 ± 30.6
.012 b.0001
Time between ingestion and acetylcysteine administration (h) Baseline SCr (mg/dL) Admission sodium Admission ammonia
12.6 ± 11.1
35.4 ± 23.9
b.0001
0.79 ± 0.1 138.9 ± 3.6 36.8 ± 22.7
1 ± 0.9 136.9 ± 7.2 128.9 ± 96.5
.27 .04 .005
Amount of APAP ingested (gm) Time before admission to OSH Time before admission to VUMC
⁎ Nephrotoxins: methotrexate, cyclosporine, tacrolimus, and nonsteroidal anti-inflammatory drugs; ⁎⁎Inducers: carbamazepine, phenytoin, phenobarbital, primidone, rifampin, sulfonylureas; APACHE, Acute Physiology and Chronic Health Evaluation, OSH, outside hospital.
J.L. Stollings et al. / Journal of Critical Care 35 (2016) 191–194 Table 2 Laboratory values and nephrotoxin administration in hospital Characteristics
Low m-MELD (b2.9) (N = 68)
Day 1 SCr 1.2 ± 0.9 Day 1 AST 233 ± 571.5 Day 3 AST 1023.5 + 2285.7 Peak AST 858.3 + 2057.3 Day 1 ALT 195 ± 560.8 Day 3 ALT 1038.3 ± 2467.9 Peak ALT 677.6 ± 2011.8 Day 1 INR 1.1 ± 0.2 Day 3 INR 1.4 ± 0.8 Highest INR 1.4 ± 0.6 Day 1 Lactate 7.7 ± 27.8 Day 3 Lactate 1.8 ± 0.9 Day 1 Low RASS −2 ± 2 Day 3 Low RASS −1 ± 1 Day 1 CAM-ICU+ 25 (37%) Day 3 CAM-ICU+ 14 (30%) Co-nephrotoxins administration Aminoglycosides 0 (0)%) NSAIDs 13 (19%) IV Contrast 4 (6%)
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Table 4a Logistic regression for variables associated with the development of acute kidney injury
High m-MELD (≥2.9) (N = 70)
P
2.7 ± 2.2 mg/dL 4641.7 + 4527.4 2461.0 + 4272.0 6594.1 + 4841.2 3624.9 + 3325.3 2757.4 + 2666 4802.6 + 3960.5 3.3 + 1.9 2.9 + 2.1 4.7 + 3.1 8.6 + 7.9 5.5 + 5.4 −2 ± 2 −1 ± 2 21 (30%) 23 (33%)
b.0001 b.0001 .03 b.0001 b.0001 .002 b.0001 b.0001 b.0001 b.0001 .79 .16 .06 .07 .10 .12
0 (0%) 7 (18%) 8 (12%)
1 .04 .16
ALT, alanine aminotransferase; IV, intravenous.
group (Table 2). Maximum change in SCr, time between ingestion and peak SCr, and requirement for new dialysis were all lower in the low m-MELD group as compared to high m-MELD group. Further, renal failure resolved in 2 (11%) of the patients in the low m-MELD group as compared to only 19 (41%) of the patients in the high mMELD group, P≤ .0001 (Table 3). Day 1 and peak transaminases were lower in the patients presenting with a m-MELD score below 2.9. Day 1, Day 3, and highest INR were all lower in the low m-MELD group (Table 2). Fewer patients in the low mMELD modified group were treated with vasopressors compared to the high m-MELD group (9 [3%] vs 25 [37%], P= .002) (Table 3). The mean days 1 and 3 lactate, days 1 and 3 lowest Richmond Agitation Sedation Scale (RASS), days 1 and 3 Confusion Assessment in the intensive care unit (CAM-ICU), and administration of nephrotoxins with the exception of nonsteroidal anti-inflammatory drugs did not differ between groups (Table 2). The occurrence of hypoglycemia (6 [9%] versus 9 [13%], P= .49) was not different between groups. The mean number of patients that received a liver transplant (0 [0%] versus 1 [1%], P= 1) did not differ between groups. The mean ICU length of stay (3.4 ± 2.1 vs 6.0 ± 5.8, Pb .002) and hospital length of stay (4.7 ± 3.8 vs 8.5 ± 8.3, Pb .005) were both longer in the high m-MELD group. The low m-MELD group had lower 28 day mortality (2 [3%] vs 14 [20%], P= .002) (Table 3).
Table 3 Outcomes Characteristics
Low m-MELD High m-MELD P (≥2.9) (b2.9) (N = 70) (N = 68)
Liver transplant Delta SCr (mg/dL) Time between ingestion and peak Scr (h) AKI New dialysis Renal failure resolved Ventilation Vasopressor use Hypoglycemia ICU length of stay (d) Hospital length of stay (d) 28-day mortality
0 (0%) 0.2 ± 0.3 26.7 + 40.6 18 (26%) 1 (1%) 2 (11%) 34 (52%) 6 (9%) 6 (9%) 3.4 ± 2.1 4.7 + 3.8 2 (3%)
1 (1%) 2.7 + 3.3 63.2 + 50.6 46 (69%) 17 (25%) 19 (41%) 36 (54%) 25 (37%) 9 (13%) 6.0 + 5.8 8.5 + 8.3 14 (20%)
.34 b.0001 b.0001 b.0001 b.0001 b.0001 .49 .002 .49 .002 .005 .002
Characteristics
P
Odds ratio
95% CI
1st APAP level (μg/mL) Time after ingestion 1st APAP level drawn m-MELD Day 1 Time after ingestion 1st dose NAC given Admission ammonia Admission AST
0.26 0.58 0.51 0.71 0.088 0.74
1.01 1.03 1.15 1.02 1.03 1.00
.98–1.02 .93–1.115 0.76–1.76 0.92–1.12 0.99–1.07 .99–1.00
AST, aspartate aminotransferase.
There were not significant independent factors associated with the development of AKI in logistic regression analysis (Table 4a). There were no significant independent factors associated with change in creatinine during hospitalization in linear regression analysis (Table 4b). 4. Discussion Our study found that patients with worse liver function are more likely to have AKI and worse kidney injury. In addition, they are also more likely to experience persistence of renal failure. Furthermore, there were no significant independent factors associated with the development of AKI or change in creatinine during hospitalization. Case series and studies investigating different etiologies of acute hepatic failure represent the majority of data associating APAP with AKI [3,10-17]. A retrospective evaluation of 302 patients admitted to a tertiary referral liver intensive therapy unit (LITU) with APAP-induced hepatotoxicity was conducted between 2000 and 2007. AKI developed in 89% of patients. Vasopressor use, mechanical ventilation, admission phosphate, admission sodium, Day 3 lactate, and Day 3 hematocrit were all associated with the development of AKI. However, all patients admitted to the LITU had severe hepatotoxicity with metabolic acidosis, coagulopathy, renal failure, hypoglycemia, encephalopathy, and thrombocytopenia [5]. Most patients in the low m-MELD group in our study would not have met criteria for admission to the LITU in that study due to absence of coagulopathy, renal failure, and hypoglycemia. N-acetylcysteine (NAC) has an established role to prevent hepatic necrosis associated with APAP overdose. However, NAC has not been shown to be beneficial in preventing nephropathy. Current case reports have not shown any difference in peak creatinine levels between patients treated and those not treated with NAC [12,18]. Paradoxically, it has been suggested that NAC may even enhance APAP-induced nephrotoxity. It is hypothesized that both renal and hepatic toxicity are secondary to the local production of a quinone imine. The direct metabolite of APAP p-aminophenal is the likely nephrotoxin after oxidation to a quinone imine intermediate. In addition, the conjugation of the quinone imine with glutathione has been shown to produce even more potent nephrotoxins. Thus, administration of NAC may worsen APAPinduced nephrotoxicity by increasing glutathione levels [19]. However, a small case series did not find worsened renal failure with the use of NAC [13]. Our study has several strengths. This is one of the largest cohort studies evaluating AKI in patients admitted after APAP overdose. In addition, this is the first study to our knowledge to evaluate renal dysfunction in patients with less and more severe liver dysfunction Table 4b Linear regression for variables associated with change in creatinine Characteristic
P
Odds ratio
1st APAP level (μg/mL) Time after ingestion 1st APAP level drawn m-MELD day 1 Time after ingestion 1st dose NAC given Admission ammonia Admission AST
.54 .63 .57 .65 .53 .81
1.01 4.44 0.17 0.39 1.08 1.00
AST, aspartate aminotransferase.
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after APAP overdose. All definitions including acute renal failure AKI, peak SCr, and change in SCr were well defined. Although the m-MELD has never been prospectively validated and is not a traditionally used or accepted scoring system, usage of the m-MELD was appropriate due to the MELD's reliance on SCr. The m-MELD does not include SCr thus allowing the patients to be divided into two groups based on severity of liver disease allowing for an independent evaluation of AKI between groups. Factors that may potentiate hepatic injury after APAP overdose, such as use of drugs that induce the cytochrome p-450 enzyme system and chronic alcohol ingestion, were included in our evaluation. Given that hepatic encephalopathy grade is not routinely documented in all patients with liver failure, the authors included the lowest RASS score and the patient's CAM-ICU status on Days 1 and 3 as surrogates of encephalopathy. There are a few limitations to our study that should be recognized. The study was at a single center and retrospective in design. However, this study involves a large heterogeneous cohort of patients admitted to a large academic medical center over a 5-year time period. This study relied on the patient or surrogate's ability to state accurate information and health care workers to document this information with regards to the amount of APAP ingested, the time course in which the APAP was ingested, and any co-ingestants taken prior to presentation. This reliance on surrogate reporting is standard for studies involving timing and quantity of overdoses. Further, most of these patients had never presented to (VUMC) prior to admission for APAP overdose resulting in a lack of availability of baseline renal function. Baseline SCr was available in 21 patients (32%) in the low m-MELD group and 17 patients (26%) in the high m-MELD group. Only one patient in this study had known chronic kidney disease and most patients had normal renal function at discharge. Similarly, another large study evaluating AKI after APAP overdose also was unable to obtain baseline SCr in most patients [5]. Lastly, renal biopsies were not performed in any of the patients in our study. Although, histopathological examination of APAP induced nephropathy has characteristic features, renal biopsies are not routinely performed in most patients after APAP overdose [18].
5. Conclusion Although not exclusive to patients with higher m-MELD scores, AKI is more common and severe in these patients. However, more than 25% of patients with lower m-MELD scores also develop AKI despite presenting significantly earlier in course of their overdose. There were no significant independent factors associated with the development of AKI or change in creatinine during hospitalization.
Acknowledgments Jeffrey Gaylon, PharmD, Christopher T. Colanero, PharmD, and Maheen Masood, PharmD Candidate assisted with data collection while they were students at Lipscomb University College of Pharmacy (JG and MM) and University of Tennessee College of Pharmacy (CC). References [1] Hodgman MJ, Garrard AR. A review of acetaminophen poisoning. Crit Care Clin 2012;28(4):499–516. [2] Mowry JB, Spyker DA, Cantilena Jr LR, McMillan N, Ford M. 2013 annual report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 31st annual report. Clin Toxicol 2014;52(10):1032–283. [3] Larson AM, Polson J, Fontana RJ, Davern TJ, Lalani E, Hynan LS, et al. Acetaminopheninduced acute liver failure: results of a United States multicenter, prospective study. Hepatology 2005;42(6):1364–72. [4] Mazer M, Perrone J. Acetaminophen-induced nephrotoxicity: pathophysiology, clinical manifestations, and management. J Med Toxicol 2008;4(1):2–6. [5] O'Riordan A, Brummell Z, Sizer E, Auzinger G, Heaton N, O'Grady JG, et al. Acute kidney injury in patients admitted to a liver intensive therapy unit with paracetamol-induced hepatotoxicity. Nephrol Dial Transplant 2011;26(11):3501–8. [6] Campbell NR, Baylis B. Renal impairment associated with an acute paracetamol overdose in the absence of hepatotoxicity. Postgrad Med J 1992;68(796):116–8. [7] Kher K, Makker S. Acute-renal-failure due to acetaminophen ingestion without concurrent hepatotoxicity. Am J Med 1987;82(6):1280–1. [8] Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P. Acute dialysis quality initiative w: acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the second international consensus conference of the acute dialysis quality initiative (ADQI) group. Crit Care 2004;8(4):R204–12. [9] Macedo E, Bouchard J, Mehta RL. Renal recovery following acute kidney injury. Curr Opin Crit Care 2008;14(6):660–5. [10] Wilkinson SP, Moodie H, Arroyo VA, Williams R. Frequency of renal impairment in paracetamol overdose compared with other causes of acute liver damage. J Clin Pathol 1977;30(2):141–3. [11] Boutis K, Shannon M. Nephrotoxicity after acute severe acetaminophen poisoning in adolescents. J Toxicol Clin Toxicol 2001;39(5):441–5. [12] Eguia L, Materson BJ. Acetaminophen-related acute renal failure without fulminant liver failure. Pharmacotherapy 1997;17(2):363–70. [13] Mour G, Feinfeld DA, Caraccio T, McGuigan M. Acute renal dysfunction in acetaminophen poisoning. Ren Fail 2005;27(4):381–3. [14] von Mach MA, Hermanns-Clausen M, Koch I, Hengstler JG, Lauterbach M, Kaes J, et al. Experiences of a poison center network with renal insufficiency in acetaminophen overdose: an analysis of 17 cases. Clin Toxicol 2005;43(1):31–7. [15] Leithead JA, Ferguson JW, Bates CM, Davidson JS, Lee A, Bathgate AJ, et al. The systemic inflammatory response syndrome is predictive of renal dysfunction in patients with non-paracetamol-induced acute liver failure. Gut 2009;58(3):443–9. [16] Bagshaw SM, George C, Bellomo R, Committee ADM. Early acute kidney injury and sepsis: a multicentre evaluation. Crit Care 2008;12(2):R47. [17] Bagshaw SM, George C, Gibney RT, Bellomo R. A multi-center evaluation of early acute kidney injury in critically ill trauma patients. Ren Fail 2008;30(6):581–9. [18] Blakely P, Mcdonald BR. Acute-renal-failure due to acetaminophen ingestion - a case-report and review of the literature. J Am Soc Nephrol 1995;6(1):48–53. [19] Jones AF, Vale JA. Paracetamol poisoning and the kidney. J Clin Pharm Ther 1993; 18(1):5–8.
Contents lists available at ScienceDirect
Journal of Critical Care journal homepage: www.jccjournal.org
Incidence and characterization of acute kidney injury after acetaminophen overdose Joanna L. Stollings, PharmD, FCCM, BCPS, BCCCP a,⁎, Arthur P. Wheeler, MD b,1, Todd W. Rice, MD, MSc b a b
Department of Pharmaceutical Services, Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN 37232, USA Division of Allergy/Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, 1211 Medical Center Drive, Nashville, TN 37232, USA
a r t i c l e
i n f o
a b s t r a c t
Keywords: Acetaminophen Acetylcysteine Acute renal failure Overdose Creatinine
Purpose: Acute kidney injury (AKI) occurs in 2–10% of patients with acetaminophen (APAP) overdose. Elevation in creatinine (SCr) typically occurs 2 to 5 days after ingestion, with a mean peak on day 7, and normalization over a month. However, it remains unclear whether renal impairment occurs without hepatotoxicity. We hypothesized that APAP-associated acute renal failure occurs in patients with and without severe liver dysfunction after APAP overdose. Materials and methods: We retrospectively evaluated all patients admitted to the Medical Intensive Care Unit at a tertiary hospital and received acetylcysteine between June 2009 and December 2014. Of the 303 patients meeting these criteria, 139 of these patients received acetylcysteine for APAP overdose. Of these patients, 138 had Model for End-Stage Liver Disease (MELD) Scores on Day 1 of admission. Using a modified MELD (m-MELD) score, only containing total bilirubin and international normalized ratio not the SCr, the median m-MELD score was calculated. Patients with m-MELD scores below the median were compared to those with scores above the median (low m-MELD score b2.9 or high m-MELD score N2.9). Results: Baseline demographics were similar in the two groups with the exception of more hypertension in the low m-MELD group (24 vs 7%; P= .02). Time to admission was shorter in the low m-MELD group (7.9 ± 9.3 vs. 25.7 ± 29.2 hours; P= .001). The mean admission APAP level was 96.9 (±119) μg/mL in the low compared to 52.3 (±85.3) μg/mL in the high m-MELD group (P= .012). Day one SCr (1.2 ± 0.9 vs 2.7 ± 2.2 mg/dL; Pb .0001) and change from baseline to highest SCr (0.2 ± 0.3 vs. 2.7 ± 3.3 mg/dL; Pb .0001) were both lower in the low m-MELD group compared to the high m-MELD group. In addition, renal failure resolved upon discharge in all 2 patients (3%) with AKI in the low m-MELD group as compared to only 19 patients (44%) in the high mMELD group. Conclusions: Mean day one SCr, maximum change in SCr, and lack of renal failure resolution were higher in patients with higher m-MELD scores. However, patients with low m-MELD scores presented much earlier than patients with high m-MELD scores and 26% developed AKI. © 2016 Elsevier Inc. All rights reserved.
1. Background
Failure Study Group were due to APAP toxicity making APAP the number one cause of liver failure in the United States [1]. APAP induced liver failure has been extensively studied [3]. However, extrahepatic effects of APAP overdoses such as acute kidney injury (AKI) are not widely discussed in the literature. AKI occurs in 2% to 10% of patients after APAP overdose [4]. However, one study reported that 79% of patients admitted to a tertiary referral liver intensive therapy unit developed AKI after APAP overdose [5]. Elevation in creatinine (SCr) typically occurs 2 to 5 days after ingestion, with a mean peak on day 7, and normalization over a month [4]. The proposed mechanism for APAP induced renal tubular damage is through the toxic metabolite N-acetyl-pbenzoquinoone-imine (NAPQI), produced via APAP metabolism by cytochrome P-450 isoenzymes present in the kidney. At therapeutic doses, less than 5% of APAP is metabolized to NAPQI. However, after
In 2005, more than 28 billion doses of acetaminophen (APAP) containing products were dispensed [1]. The American Association of Poison Control Center's National Poison Data System reported 400 deaths in 2013 secondary to APAP or an APAP combination product [2]. Nearly half of the cases of acute liver failure in the United States Acute Liver
⁎ Corresponding author at: 1211 Medical Center Drive, BUH-131, Nashville, TN, 37232. Tel.: +1 615 343 5376. E-mail addresses: [email protected] (J.L. Stollings), [email protected] (A.P. Wheeler), [email protected] (T.W. Rice). 1 Posthumous. http://dx.doi.org/10.1016/j.jcrc.2016.06.004 0883-9441/© 2016 Elsevier Inc. All rights reserved.
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overdose, glutathione depletion results in the generation of more NAPQI reactive intermediates [4]. Although 2 case reports have demonstrated renal impairment without evidence of hepatotoxicity [6,7], systematic evaluation of risk factors for AKI with APAP overdose are lacking. This retrospective review was performed to determine if AKI associated with APAP overdose is more frequently associated with severe liver dysfunction. 2. Methods All patients admitted to the Medical Intensive Care Unit (MICU) of a large, tertiary care academic medical center who received acetylcysteine between June 2009 and December 2014 were identified through a retrospective medication review. Patients were included if they received acetylcysteine for APAP overdose and had a Measure of End Stage Liver Disease (MELD) Score recorded on day 1 of admission. Using a modified MELD (m-MELD) score, only containing total bilirubin and international normalized ratio (INR), not the SCr, the median mMELD score was calculated. Patients were divided into 2 groups (low m-MELD Group [m-MELD b2.9] and high m-MELD Group [m-MELD ≥2.9]). Patients with baseline renal dysfunction were not excluded. The Vanderbilt University Institutional Review Board approved this study with waiver of informed consent. 2.1. Study objective The primary objective was to determine if AKI was associated with higher severity of liver dysfunction. 2.2. Definitions Nephrotoxins were defined as methotrexate, cyclosporine, tacrolimus, or nonsteroidal anti-inflammatory drugs. Inducers were defined as carbamazepine, phenytoin, phenobarbital, primidone, rifampin, and sulfonylureas. AKI was defined as SCr greater than 1.5 times baseline or an increase in SCr by 0.3 mg/dL in a 48-hour period. Baseline SCr was defined as the SCr before the admission for APAP overdose. Acute overdose was defined as an ingestion of an amount greater than the maximum recommended daily dose of APAP within a 24-hour period. Chronic overdose was defined as ingestion of an amount greater than the maximum recommended daily dose of APAP for a period of time greater than a 24-hour period. Hypoglycemia was defined as a glucose value of ≤60 mg/dL. Peak SCr was defined as the highest SCr value during the patient's hospitalization. Delta SCr was defined as the change from baseline to peak SCr. Resolution of renal failure was defined as no continuation of dialysis and a SCr clearance greater than 60 mL/min [8,9]. 2.3. Data collection Baseline data collected from the medical record included demographics, past medical history, and Acute Physiology and Chronic Health Evaluation (APACHE) II score. The following data were collected with regard to APAP: time to hospital admission, type of overdose, APAP levels and acetylcysteine administration. Measures of SCr, requirement of new dialysis, development and resolution of AKI, liver function tests, mental status assessments, determinants of coagulopathy, and outcome were collected. 2.4. Statistical analysis Categorical data are reported as numbers and percentages and analyzed using χ 2 test. Continuous data are reported as means ± SD and analyzed using Student t tests. A logistic regression was performed to assess whether variables were associated with the development of AKI. A linear regression was performed to assess whether variables
were associated with the change in SCr. Variables were chosen to be placed in the regressions based off statistical significance and primary features seen with acute liver failure while ensuring not to include colinear variables such as SCr or the individual components of the mMELD. Statistical analyses were performed with SPSS Version 23 (IBM, Inc, Armonk, NY). 3. Results Acetylcysteine was administered to 303 patients admitted to the MICU between June 2009 and December 2014. Of these, 139 received acetylcysteine for APAP overdose and 138 had MELD scores calculated on day 1. 3.1. Baseline demographics and admission diagnosis The median baseline m-MELD score was 2.9 (IQR, 1.7-7.5). There was no difference in baseline demographics between the low and high mMELD groups except in hypertension (Table 1). Admission to the outside hospital (7.9 ± 9.3 vs 25.7 ± 29.2 hours, P= .001) and to Vanderbilt University Medical Center (VUMC) (11.4 ± 14.6 vs 40.4 ± 30.6 hours, Pb .0001) both occurred earlier in the low m-MELD as compared to the high m-MELD group. The low m-MELD group had more acute overdoses as compared to the high m-MELD group (63 [93%] vs 52 [76%], P= .01), although the amount of APAP ingested and the initial APAP level did not differ significantly between groups. Time until the first APAP level (8.4 ± 8.2 vs 35.1 ± 30.6 hours, P≤ .0001) and time between ingestion and acetylcysteine administration (12.6 ± 11.1 vs 35.4 ± 23.9 hours, Pb .0001) were lower in the low m-MELD group (Table 1). AKI occurred in 8 patients (26%) with an initial m-MELD score below 2.9 as compared to 46 (69%) in the high m-MELD group, Pb .0001 (Table 3). Baseline SCr was 0.8 ± 0.2 mg/dL in the low as compared to 1.0 ± 0.9 mg/dL in the high m-MELD group, P= .26 (Table 1). Day 1 SCr (1.2 ± 0.9 vs. 2.7 ± 2.2 mg/dL; Pb .0001) and peak SCr (1.4 ± 1.3 vs. 3.3 ± 2.8 mg/dL; Pb .0001) were both lower in the low m-MELD
Table 1 Baseline demographics Characteristics
Low m-MELD (b2.9) (N = 68)
High m-MELD (≥2.9) (N = 70)
P
Age Sex (female) Race (white) APACHE II Score Past medical history Diabetes mellitus Chronic kidney disease Hypertension Chronic Alcohol Ingestion Acute APAP ingestion Nephrotoxins⁎ Inducers⁎⁎
41.9 ± 14.4 37 (54%) 61 (89%) 12.6 ± 8
39.1 ± 13.9 48 (70%) 64 (91%) 11.3 ± 8.4
.39 .06 .35 .36
7 (10%) 0 (0%) 16 (24%) 9 (13.2%) 63 (93%) 6 (9%) 2 (3%) 21.3 ± 18.2 7.9 ± 9.3 11.4 ± 14.6
2 (3%) 1 (1%) 5 (7%) 16 (23%) 52 (76%) 2 (3%) 0 (0%) 22.9 ± 32.5 25.7 ± 29.2 40.4 ± 30.6
.08 .32 .02 .14 .01 .13 .15 .85 .001 b.0001
1st APAP Level (μg/mL) Time Until 1st APAP Level (h)
96.9 ± 119 8.4 ± 8.2
52.3 ± 85.3 35.1 ± 30.6
.012 b.0001
Time between ingestion and acetylcysteine administration (h) Baseline SCr (mg/dL) Admission sodium Admission ammonia
12.6 ± 11.1
35.4 ± 23.9
b.0001
0.79 ± 0.1 138.9 ± 3.6 36.8 ± 22.7
1 ± 0.9 136.9 ± 7.2 128.9 ± 96.5
.27 .04 .005
Amount of APAP ingested (gm) Time before admission to OSH Time before admission to VUMC
⁎ Nephrotoxins: methotrexate, cyclosporine, tacrolimus, and nonsteroidal anti-inflammatory drugs; ⁎⁎Inducers: carbamazepine, phenytoin, phenobarbital, primidone, rifampin, sulfonylureas; APACHE, Acute Physiology and Chronic Health Evaluation, OSH, outside hospital.
J.L. Stollings et al. / Journal of Critical Care 35 (2016) 191–194 Table 2 Laboratory values and nephrotoxin administration in hospital Characteristics
Low m-MELD (b2.9) (N = 68)
Day 1 SCr 1.2 ± 0.9 Day 1 AST 233 ± 571.5 Day 3 AST 1023.5 + 2285.7 Peak AST 858.3 + 2057.3 Day 1 ALT 195 ± 560.8 Day 3 ALT 1038.3 ± 2467.9 Peak ALT 677.6 ± 2011.8 Day 1 INR 1.1 ± 0.2 Day 3 INR 1.4 ± 0.8 Highest INR 1.4 ± 0.6 Day 1 Lactate 7.7 ± 27.8 Day 3 Lactate 1.8 ± 0.9 Day 1 Low RASS −2 ± 2 Day 3 Low RASS −1 ± 1 Day 1 CAM-ICU+ 25 (37%) Day 3 CAM-ICU+ 14 (30%) Co-nephrotoxins administration Aminoglycosides 0 (0)%) NSAIDs 13 (19%) IV Contrast 4 (6%)
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Table 4a Logistic regression for variables associated with the development of acute kidney injury
High m-MELD (≥2.9) (N = 70)
P
2.7 ± 2.2 mg/dL 4641.7 + 4527.4 2461.0 + 4272.0 6594.1 + 4841.2 3624.9 + 3325.3 2757.4 + 2666 4802.6 + 3960.5 3.3 + 1.9 2.9 + 2.1 4.7 + 3.1 8.6 + 7.9 5.5 + 5.4 −2 ± 2 −1 ± 2 21 (30%) 23 (33%)
b.0001 b.0001 .03 b.0001 b.0001 .002 b.0001 b.0001 b.0001 b.0001 .79 .16 .06 .07 .10 .12
0 (0%) 7 (18%) 8 (12%)
1 .04 .16
ALT, alanine aminotransferase; IV, intravenous.
group (Table 2). Maximum change in SCr, time between ingestion and peak SCr, and requirement for new dialysis were all lower in the low m-MELD group as compared to high m-MELD group. Further, renal failure resolved in 2 (11%) of the patients in the low m-MELD group as compared to only 19 (41%) of the patients in the high mMELD group, P≤ .0001 (Table 3). Day 1 and peak transaminases were lower in the patients presenting with a m-MELD score below 2.9. Day 1, Day 3, and highest INR were all lower in the low m-MELD group (Table 2). Fewer patients in the low mMELD modified group were treated with vasopressors compared to the high m-MELD group (9 [3%] vs 25 [37%], P= .002) (Table 3). The mean days 1 and 3 lactate, days 1 and 3 lowest Richmond Agitation Sedation Scale (RASS), days 1 and 3 Confusion Assessment in the intensive care unit (CAM-ICU), and administration of nephrotoxins with the exception of nonsteroidal anti-inflammatory drugs did not differ between groups (Table 2). The occurrence of hypoglycemia (6 [9%] versus 9 [13%], P= .49) was not different between groups. The mean number of patients that received a liver transplant (0 [0%] versus 1 [1%], P= 1) did not differ between groups. The mean ICU length of stay (3.4 ± 2.1 vs 6.0 ± 5.8, Pb .002) and hospital length of stay (4.7 ± 3.8 vs 8.5 ± 8.3, Pb .005) were both longer in the high m-MELD group. The low m-MELD group had lower 28 day mortality (2 [3%] vs 14 [20%], P= .002) (Table 3).
Table 3 Outcomes Characteristics
Low m-MELD High m-MELD P (≥2.9) (b2.9) (N = 70) (N = 68)
Liver transplant Delta SCr (mg/dL) Time between ingestion and peak Scr (h) AKI New dialysis Renal failure resolved Ventilation Vasopressor use Hypoglycemia ICU length of stay (d) Hospital length of stay (d) 28-day mortality
0 (0%) 0.2 ± 0.3 26.7 + 40.6 18 (26%) 1 (1%) 2 (11%) 34 (52%) 6 (9%) 6 (9%) 3.4 ± 2.1 4.7 + 3.8 2 (3%)
1 (1%) 2.7 + 3.3 63.2 + 50.6 46 (69%) 17 (25%) 19 (41%) 36 (54%) 25 (37%) 9 (13%) 6.0 + 5.8 8.5 + 8.3 14 (20%)
.34 b.0001 b.0001 b.0001 b.0001 b.0001 .49 .002 .49 .002 .005 .002
Characteristics
P
Odds ratio
95% CI
1st APAP level (μg/mL) Time after ingestion 1st APAP level drawn m-MELD Day 1 Time after ingestion 1st dose NAC given Admission ammonia Admission AST
0.26 0.58 0.51 0.71 0.088 0.74
1.01 1.03 1.15 1.02 1.03 1.00
.98–1.02 .93–1.115 0.76–1.76 0.92–1.12 0.99–1.07 .99–1.00
AST, aspartate aminotransferase.
There were not significant independent factors associated with the development of AKI in logistic regression analysis (Table 4a). There were no significant independent factors associated with change in creatinine during hospitalization in linear regression analysis (Table 4b). 4. Discussion Our study found that patients with worse liver function are more likely to have AKI and worse kidney injury. In addition, they are also more likely to experience persistence of renal failure. Furthermore, there were no significant independent factors associated with the development of AKI or change in creatinine during hospitalization. Case series and studies investigating different etiologies of acute hepatic failure represent the majority of data associating APAP with AKI [3,10-17]. A retrospective evaluation of 302 patients admitted to a tertiary referral liver intensive therapy unit (LITU) with APAP-induced hepatotoxicity was conducted between 2000 and 2007. AKI developed in 89% of patients. Vasopressor use, mechanical ventilation, admission phosphate, admission sodium, Day 3 lactate, and Day 3 hematocrit were all associated with the development of AKI. However, all patients admitted to the LITU had severe hepatotoxicity with metabolic acidosis, coagulopathy, renal failure, hypoglycemia, encephalopathy, and thrombocytopenia [5]. Most patients in the low m-MELD group in our study would not have met criteria for admission to the LITU in that study due to absence of coagulopathy, renal failure, and hypoglycemia. N-acetylcysteine (NAC) has an established role to prevent hepatic necrosis associated with APAP overdose. However, NAC has not been shown to be beneficial in preventing nephropathy. Current case reports have not shown any difference in peak creatinine levels between patients treated and those not treated with NAC [12,18]. Paradoxically, it has been suggested that NAC may even enhance APAP-induced nephrotoxity. It is hypothesized that both renal and hepatic toxicity are secondary to the local production of a quinone imine. The direct metabolite of APAP p-aminophenal is the likely nephrotoxin after oxidation to a quinone imine intermediate. In addition, the conjugation of the quinone imine with glutathione has been shown to produce even more potent nephrotoxins. Thus, administration of NAC may worsen APAPinduced nephrotoxicity by increasing glutathione levels [19]. However, a small case series did not find worsened renal failure with the use of NAC [13]. Our study has several strengths. This is one of the largest cohort studies evaluating AKI in patients admitted after APAP overdose. In addition, this is the first study to our knowledge to evaluate renal dysfunction in patients with less and more severe liver dysfunction Table 4b Linear regression for variables associated with change in creatinine Characteristic
P
Odds ratio
1st APAP level (μg/mL) Time after ingestion 1st APAP level drawn m-MELD day 1 Time after ingestion 1st dose NAC given Admission ammonia Admission AST
.54 .63 .57 .65 .53 .81
1.01 4.44 0.17 0.39 1.08 1.00
AST, aspartate aminotransferase.
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after APAP overdose. All definitions including acute renal failure AKI, peak SCr, and change in SCr were well defined. Although the m-MELD has never been prospectively validated and is not a traditionally used or accepted scoring system, usage of the m-MELD was appropriate due to the MELD's reliance on SCr. The m-MELD does not include SCr thus allowing the patients to be divided into two groups based on severity of liver disease allowing for an independent evaluation of AKI between groups. Factors that may potentiate hepatic injury after APAP overdose, such as use of drugs that induce the cytochrome p-450 enzyme system and chronic alcohol ingestion, were included in our evaluation. Given that hepatic encephalopathy grade is not routinely documented in all patients with liver failure, the authors included the lowest RASS score and the patient's CAM-ICU status on Days 1 and 3 as surrogates of encephalopathy. There are a few limitations to our study that should be recognized. The study was at a single center and retrospective in design. However, this study involves a large heterogeneous cohort of patients admitted to a large academic medical center over a 5-year time period. This study relied on the patient or surrogate's ability to state accurate information and health care workers to document this information with regards to the amount of APAP ingested, the time course in which the APAP was ingested, and any co-ingestants taken prior to presentation. This reliance on surrogate reporting is standard for studies involving timing and quantity of overdoses. Further, most of these patients had never presented to (VUMC) prior to admission for APAP overdose resulting in a lack of availability of baseline renal function. Baseline SCr was available in 21 patients (32%) in the low m-MELD group and 17 patients (26%) in the high m-MELD group. Only one patient in this study had known chronic kidney disease and most patients had normal renal function at discharge. Similarly, another large study evaluating AKI after APAP overdose also was unable to obtain baseline SCr in most patients [5]. Lastly, renal biopsies were not performed in any of the patients in our study. Although, histopathological examination of APAP induced nephropathy has characteristic features, renal biopsies are not routinely performed in most patients after APAP overdose [18].
5. Conclusion Although not exclusive to patients with higher m-MELD scores, AKI is more common and severe in these patients. However, more than 25% of patients with lower m-MELD scores also develop AKI despite presenting significantly earlier in course of their overdose. There were no significant independent factors associated with the development of AKI or change in creatinine during hospitalization.
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