a b s t r a c t

Objective: Limited data exist on the incidence of contrast induced nephropathy (CIN) and its impact on in- hospital prognosis of patients diagnosed with Acute pulmonary embolism using contrast computerized to- mography pulmonary angiography (CTPA). In this study, we examined the frequency of nephropathy after CTPA in APE patients and its link to in-hospital adverse outcomes.

Methods: This was a retrospective study of 189 patients (mean age 67 + 16 years, 48% male) with APE who underwent CTPA. CIN was defined as a >= 0.5 mg/dl and/or >= 25% increase in serum Creatinine levels N 48 hours after CTPA. Patients were divided into two groups according to the presence or absence of CIN to compare clinical characteristics, risk factors, and In-hospital adverse events.

Results: Twenty-four (13%) of the patients were diagnosed with CIN. Patients with CIN were older (73 +- 17 vs. 67 +- 15 years, P = .01) and had higher rates of heart failure (17% vs. 6%, P = .04). Preexisting renal dysfunction and advanced age were found to be independent predictors of CIN (OR: 4.2, 95% CI: 1.5-11.9, P = .006; OR: 3.2, 95% CI: 1.1-9.8, P = .03 respectively). The in-hospital Adverse event rate was significantly higher in patients with CIN (16.7% vs. 2.4%, P = .001). A multivariate analysis revealed CIN as an independent predictor of in-hospital adverse event rate (OR: 6.1, 95%CI: 1.2-29.3, P = .02).

Conclusion: CIN is associated with a higher in-hospital adverse event rate in APE patients diagnosed using CTPA. This is first large study to focus specifically on CIN in patients diagnosed with APE using CTPA.

(C) 2016

1. Introduction

Acute pulmonary embolism is the third most common cause of Cardiovascular death after coronary artery disease and cerebrovascu- lar disease [1]. Mortality rates are reportedly as high as 50% in hemody- namically impaired patients [2]. Patients who are hemodynamically stable at presentation have early mortality rates up to 15% [3]. Therefore,

Abbreviations: APE, Acute pulmonary embolism; CTPA, Computerized tomography pulmonary angiography; CIN, Contrast-induced nephropathy; eGFR, Estimated glomeru- lar filtration rates.

? Funding: The author(s) received no financial support for the research, authorship,

and/or publication of this article.

?? Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

* Corresponding author at: Cihadiye Street, No: 61/10 A-Blok, Altintepe, Maltepe-

Istanbul, 34840. Tel.: +90 505 4748 2588; fax: +90 216 444 52 57.

E-mail addresses: [email protected] (S. Yazici), [email protected] (T. Kiris), [email protected] (A. Emre), [email protected] (U.S. Ceylan), [email protected] (S. Akyuz), [email protected] (A.O. Uzun), [email protected] (R. Haci), [email protected] (S. Terzi), [email protected] (A. Erdem), [email protected] (K. Yesilcimen).

early diagnosis and treatment are necessary to improve the prognosis of APE patients. Computerized tomography pulmonary angiography (CTPA) is commonly used in diagnosing APE because of its high sensitivity and specificity [4]. Its main advantages are its round the clock accessibil- ity, diagnosing capabilities and use in differential diagnosis of patients with chest pain. CTPA also provides prognostic information, such as right ventricular dysfunction and thrombus load [5,6]. Despite these ad- vantages, there are adverse of effects of CTPA, including radiation and contrast media exposure. Contrast nephropathy is generally defined as a transient impairment of renal function after the administration of contrast media used in diagnostic and invasive procedures [7]. Renal impairment due to contrast nephropathy is temporary, and renal replacement therapy is typically not necessary but is linked with increased mortality rates [8-10]. There is limited data about the effects of CTPA on the renal func- tions of APE patients. The patient participants in most studies relating to the effects of CTPA on renal functions are suspected of having APE, but only 20% are actually diagnosed with APE [11-13].

In this study, we examined the frequency of nephropathy after CTPA in APE patients and its link to in-hospital adverse outcomes. We also in- vestigated nephropathy risk factors in these patients.

http://dx.doi.org/10.1016/j.ajem.2016.03.053

0735-6757/(C) 2016

1248 S. Yazici et al. / American Journal of Emergency Medicine 34 (2016) 1247-1250

1. Methods
   1. Study design and patients

The data of APE in-patients diagnosed using CTPA between 2011 and 2015 were scanned retrospectively. The study was approved by the local scientific board of our hospital. Informed consent was waived be- cause it was a retrospective study.

The hospital database was scanned, and 222 patients diagnosed with APE were found. Patients diagnosed using methods other than CTPA (n = 12), patients who received renal replacement therapy (n = 1), pa- tients who presented with cardiogenic shock (n = 10), patients with only one creatinine measurement during follow-up (n = 8), patients taking nephrotoxic drugs (n = 1), and patients under the age of 18 (n = 1) were excluded. The remaining 189 patients were enrolled in the study. Presentation symptoms, demographic characteristics, illness history, vital signs (systolic blood pressure, heart rate), and transthorac- ic echocardiography findings were recorded on the study form. Treat- ment and complications during follow-up were noted.

Setting and definitions

Blood samples were drawn for a complete blood count and chemis- try panel from the vein used for contrast administration during CTPA. CT examinations were performed using a 16-slice multidetector CT scanner (Somatom Sensation; Siemens Medical Systems, Erlangen, Germany).

According to our radiology clinic’s CTPA protocol, a Bolus infusion of 85 ml iodinated contrast agent (350 mg I/ml, OMNIPAQUE(TM), GE Healthcare Ireland, Cork, Ireland) was administered intravenously at 4 ml/s using an automatic injector via an antecubital vein. CTPA reports were examined by an expert radiologist. Creatinine levels were mea- sured using the spectrophotometric method.

The patient’s creatinine level on admission served as the baseline value. An absolute increase in peak serum creatinine >= 0.5 mg/dl and/ or >= 25% increase relative to baseline at least 48 hours following the CTPA scan was defined as CIN [14]. Furthermore, using baseline serum creatinine levels and the “epidemiology collaboration” formula, esti- mated glomerular filtration rates (eGFR) were calculated and levels below 60 ml/min/1.73 m2 were accepted as preexisting renal dysfunc- tion [15]. Cardiogenic shock was defined as sustained hypotension (sys- tolic Blood pressure b 90 mm Hg lasting N 15 min) without the presence of volume loss or arrhythmias [16]. Major bleeding was de- fined as bleeding causing a drop of 2 gr/dl or more in the baseline hemo- globin level; intracranial, intraocular, or retroperitoneal bleeding; and bleeding requiring two or more blood transfusions [17].

CIN or renal replacement therapy were primary ending points. In- hospital adverse events (death, hemodynamic instability requiring pos- itive inotropic agents, hypoxia requiring mechanical ventilation, major bleeding) were secondary end points.

Statistical analysis

carried out using the Statistical Package for Social Sciences software (SPSS 16.0 for Windows, SPSS Inc., Chicago, Illinois, USA).

1. Results
   1. Baseline characteristics

The mean patient age was 67 +- 16 years, and 91(48%) of the pa- tients were male. The most frequent symptom was dyspnea (75%) at the time of hospital admission. The baseline clinical and laboratory find- ings of the patients are shown in Table 1. The median value of the period to reach peak creatinine value was 48 hours (IQR 96). A thrombolytic agent was administered to 46 (24%) patients. The mean length of hospi- talization was 7.3 +- 2.8 days. Ninety-four percent of the patients were prescribed vitamin K antagonists at discharge.

Prevalence and predictors of CIN

Sixty-nine (36.5%) of the patients had baseline eGFR levels below 60 ml/min/1.73 m2, and 24 (13%) were diagnosed with CIN. The mean baseline serum creatinine level increased from 0.93 +- 0.3 mg/dl to a mean of 1.33 +- 0.4 mg/dl in patients with CIN (P b .0001). None of the CIN patients had need of renal replacement therapy. A multivariate logis- tic regression analysis showed that basal eGFR under 60 ml/min/1.73 m2 (OR: 3.2, 95%CI: 1.1-9.8, P = .033) and age over 75 (OR: 4.2, 95%CI:

1.5-11.9, P = .006) were independently related to CIN occurrence. The re- sults of multivariate analysis are shown in Table 2.

Adverse events and CIN

In-hospital adverse events occurred in 8 (4%) patients (3 deaths, 2 major bleedings, 2 needed mechanical ventilation support, and 1

Table 1

Baseline Characteristics

Variable	All patients	Gruop1 CIN (-)	Group 2 CIN (+)	p value
	n = 189	n = 165	n = 24
Age (years) (mean +- SD)	67 +- 16	67 +- 15	73 +- 17	0.01
Female gender (n, %)	98 (52%)	83 (50%)	15 (63%)	0.26
Diabetes mellitus (n, %)	45 (24%)	36 (22%)	9 (38%)	0.09
Hypertension (n, %)	91 (48%)	75 (46%)	16 (67%)	0.052
History of CAD (n, %)	28 (15%)	25 (15%)	3 (13%)	0.73
History of CHF (n, %)	13 (7%)	9 (6%)	4 (17%)	0.04
History of CVD (n, %)	7 (4%)	6 (4%)	1 (4%)	0.89
Smoking (n, %)	29 (15%)	28 (17%)	1 (4%)	0.10
Chronic pulmonary disease (n, %)	11 (6%)	8 (5%)	3 (13%)	0.13
Cancer (n, %)	7 (4%)	5 (3%)	2 (8%)	0.19
Recent surgery (n, %)	31 (16%)	28 (17%)	3 (13%)	0.58
History of PE (n, %)	7 (4%)	5 (3%)	2 (8%)	0.19
Systolic blood pressure (mmHg)	125 +- 22	124 +- 20	128 +- 25	0.85
(mean +- SD)
Heart rate (beat/minute)	93 +- 17	93 +- 17	94 +- 17	0.68
(mean +- SD) Troponin-I ng/dl (media, IQR)	0.15 (0.6)	0.15 (0.6)	0.21 (0.8)	0.32
D-dimer pg/ml (median, IQR)	2823	2933	2237	0.29
	(4757)	(4923)	(3345)
Baseline eGFR ml/min/1.73	71 +- 25	70 +- 25	73 +- 27	0.60
(mean +- SD)
Baseline Creatinine mg/dl	1.0 +- 0.3	1.0 +- 0.3	0.93 +- 0.3	0.057
(mean +- SD)

Numeric data were checked for the normal distribution assumption using the Kolmogorov-Smirnov test. Continuous variables showing nor- mal distribution were given standard deviation (SD) or mean values, and an independent t test was used to compare the data between groups. Continuous variables showing non-normal distribution were given medi- an and quartile values; these data were compared between groups using a Mann-Whitney U test. The eGFR values of the groups before and after CTPA were compared using a paired t test. Categorical variables were given ratios and numbers and compared using a chi-square test. To deter- mine independent predictors of primary and secondary end points, vari-

Peak Creatinine mg/dl (mean +- SD)

Hemoglobin gr/dl (mean +- SD)	12.8 +- 1.9	12.9 +- 1.9	12.6 +- 2.1	0.55
Serum glucose mg/ml (mean +- SD)	150 +- 59	145 +- 52	177 +- 91	0.20
PESI score (mean +- SD)	82 +- 22	81 +- 21	91 +- 28	0.04
LVEF (%) (mean +- SD)	57 +- 3	57 +- 8	54 +- 15	0.61
Thrombolytic treatment (n, %)	46 (24%)	43 (26%)	3 (13%)	0.14

1.1 +- 0.4 1.0 +- 0.3 1.3 +- 0.4 0.002

ables with P b .1 in univariate analysis were included in both models, and multivariate logistic regression analysis was performed. A p value b.05 was considered statistically significant. All statistical studies were

CAD: coronary artery disease, CHF: congestive heart failure, CIN: contrast induced ne- phropathy, CVD: cerebrovascular disease, IQR: inter quartile range, LVEF: left ventricular ejection fraction, PESI: pulmonary embolism severity index.

S. Yazici et al. / American Journal of Emergency Medicine 34 (2016) 1247-1250

1249

Table 2

Multivariate analysis prediction of CIN

Table 3

Univariate and multivariate analysis of in-hospital adverse envents

OR 95% CI p value

Age N 75 years 4.2 1.5 11.9 0.006

Variable Univariate

OR (95CI%)

p value

Multivariate OR (95%CI)

p value

Baseline eGFR b60 ml/min/1.73m2	3.2	1.1	9.8	0.033		Age N 75 year	5.4	1.07-27.9	0.041	3.2	0.58-18.3	0.1
History of DM	1.7	0.6	4.7	0.3		Male gender	1.8	0.42-7.93	0.4
History of HT	2.0	0.5	8.3	0.1		History of Cancer	4.1	0.44-39.4	0.2
Hemoglobin gr/dl	1.0	0.7	1.2	0.9		History of CAD	1.2	0.14-10.3	0.8
History of CHF	2.0	0.5	8.3	0.3		History of CHF	0.9	0.92-0.98	0.4
CHF: congestive heart failure, CI: confidence interval, DM: diabetes mellitus, HT: hyperten- sion, OR: odds ratio.					History of Hypertension Historf of Diabetes mellitus Systolic blood pressure (mmHg)		3.3 3.4 1.0	0.66-17.2 0.81-14.2 0.98-1.04	0.14 0.09 0.3	1.8	0.38-8.90	0.4

needed positive inotropic support). The number of patients reaching secondary ending points was significantly higher in the CIN group (16.7% vs. 2.4%, P = .001); see Figure. Based on the multivariate analysis, CIN occurrence was significantly related to in-hospital adverse events (OR: 6.1, 95%CI: 1.2-29, P = .02, Table 3).

Heart rate (beat/minute)	1.0	0.96-1.04	0.7
Respiratory ratre	1.1	0.89-1.59	0.2
(breath/minute)

eGFRb 60 ml/min/1.73m2	3.0	0.70-13.1	0.13
Hemoglobin (gr/dl)	0.9	0.65-1.34	0.7
CIN	8.0	1.86-34.7	0.005	6.1	1.29-29.3	0.02
cTn-I (+)	1.0	1.02-1.12	0.049	1.1	0.89-1.46	0.2
LVEF (%)	0.9	0.91-1.08	0.9
Thrombolytic treatment	1.0	0.20-5.32	0.9

1. Discussion

The major findings of our study are: 1) CIN after CTPA frequency in APE patients was 13%; 2) preexisting renal dysfunction and advanced age increase the risk of CIN independent of other variables; and 3) CIN was found to be an independent predictor of poor clinical outcome dur- ing the in-hospital period.

CIN incidence varies between different patient groups. CIN frequen- cy after elective coronary angiography and percutaneous coronary in- tervention is 3.3%-14.5%, whereas CIN occurs in 19% of Acute myocardial infarction patients undergoing percutaneous coronary in- tervention (PCI) [8,9,18]. CIN frequency after contrast CT was reported as 4.9% and 6% in two meta-analyses [19,20]. CIN after a CTPA scan was reported to be more frequent. Mitchel et al. studied 354 patients undergoing CTPA and found CIN frequency to be 12% [12]. Doganay et al. studied 122 APE patients and found CIN frequency to be 13.2% [21]. There is a correlation between our study results and the current lit- erature. CIN being more frequent in CTPA than general contrast CT scans can probably be attributed to the specific disease conditions of APEs. In- creased right ventricular pressure due to APE may be responsible for CIN development. Increased right ventricular pressure leads to increased renal venous pressure, which may have a role in Renal damage. Hypoxia seen in APE may be another cause of renal ischemia and CIN. Prolonged vasoconstriction of the vasa recta-which is the main blood supplier of

CAD: coronary artery disease, CHF: congestive heart failure, CI: confidence interval, CIN: contrast induced nephropathy, cTn-I: cardiac troponin-I, eGFR: estimated glomerular fil- tration rate, LVEF: left ventricular ejection fraction, OR: odds ratio.

the deep outer renal medulla-is a component of CIN physiopathology, and in APE patients vasoconstriction may last longer and be stronger [22]. The levels of potent vasoconstrictors, such as thromboxane and se- rotonin, are shown to be higher in APE [23,24].

Many studies have reported the risk factors for CIN development to be preexisting chronic kidney disease (CKD), diabetes mellitus , and age [25,26]. In our study, a multivariate analysis revealed that preexisting renal dysfunction and advanced age increase the risk of CIN development. Our findings are consistent with the current literature. Although a history of diabetes mellitus increases the risk of CIN development, it was statisti- cally insignificant. This was probably because the number of patients with high baseline creatinine levels is almost identical in diabetic and nondia- betic patient groups (47% vs. 33%, respectively, P = .1). Rihal et al. report similar findings in their study. They found that CIN development rates are parallel in diabetic and nonDiabetic patients with high baseline serum cre- atinine levels undergoing PCI [9].

Even though CIN occurs frequently, the need for renal replacement therapy and long-lasting renal Failure rates are 0.4% to 1% [8,27]. In our

Figure. In hospital Adverse event rates. CIN: contrast induced nephropathy.

1250 S. Yazici et al. / American Journal of Emergency Medicine 34 (2016) 1247-1250

study, none of the patients needed renal replacement therapy, but CIN was still found to be responsible for increased mortality and adverse clinical outcomes. Previous studies have stated that CIN is related to in-hospital and long-term mortality [28,29]. Because this is the first study to show a significantly increased risk for adverse events in pa- tients diagnosed with APE who develop CIN, we believe additional effort should be devoted to aggressively avoiding this post CTPA complication. We also believe further studies at other centers should evaluate this relationship.

Many reports discuss the relationship between CIN and increased mortality and adverse events, but the underlying mechanism is still not clear. As stated above, in CIN patients the need for renal replacement therapy is low, and therefore it cannot be the cause of increased mortal- ity. Most adverse events in CIN patients are of cardiovascular origin [30]. Risk factors for CIN, such as age, DM, and CKD, are also Cardiovascular risk factors; therefore, increased Cardiovascular adverse events may be because of intensified risk factors. Levy et al. found that among patients with the same baseline comorbidities the ones suffering from CIN had higher mortality [31]. In our study, rates of comorbidities other than ad- vanced age and congestive heart failure were similar in both groups; therefore, increased adverse events cannot be explained only by in- creased comorbidities. Renal hypoperfusion develops after cardiac dam- age triggers renal damage [32]. Contrast agents may aggravate this damage. Renal vasoconstrictors, uremic toxins, and volume increase negatively affect Cardiac functions [33,34]. This viscous cycle may be re- sponsible for the increase in adverse events.

There are limitations in our study. First, because the data was retro- spectively collected serum albumin and urine Albumin levels, which af- fect CIN risk, may not have been measured. At the beginning, Hemodynamically stable patients were enrolled in the study, but during follow-up some of them became unstable deteriorated to instable con- dition. Renal insufficiency may be linked to hemodynamic instability, but only one patient needed positive inotropic support in the CIN group. Furthermore, serum creatinine levels increased 12 hours before Hemodynamic deterioration; therefore, we do not think this affected the study results. Last, the study analyzed only the in-hospital period; therefore, there may have been patients who suffered renal insufficien- cy after discharge. This may have led to the finding of a lower CIN inci- dence rate than actually existed.

1. Conclusion

CIN development in APE patients is independently related to worse clinical outcomes and must be watched for closely. Patients with ad- vanced age and a preexisting decrease in renal function must be moni- tored thoroughly. Maintaining hydration, stopping nephrotoxic medication, and preventing recurrent exposure to contrast medium helps to decrease CIN development and its worst clinical outcomes. De- veloping alternative diagnostic methods or modifying the dye load as more sensitive CT scanners are developed to detect APE in those pa- tients at highest risk for CIN is necessary.

Acknowledgments

The authors acknowledge Dr. Sinan Sahin for his skilful work.

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