Article, Hematology

Incidence and patterns of hemolytic anemia in acute dapsone overdose

a b s t r a c t

Background: hemolytic anemia is one of the complications related to the chronic consumption of dapsone. How- ever, in acute dapsone overdose, there have been few case reports regarding hemolytic anemia. Herein, we re- ported the prevalence and patterns of hemolytic anemia in acute dapsone overdose, and compared clinical features including mortality in the non-hemolytic anemia and the hemolytic anemia groups.

Methods: We conducted a retrospective review of 43 consecutive acute dapsone overdose cases that were diag- nosed and treated at the emergency department of the Wonju Severance Christian Hospital between January 2006 and January 2014.

Results: There were 13 male patients (30.2%) and the ages of all patients ranged from 18 to 93 years with a me- dian of 67 years. The ingested dose varied from a minimum of two 100-mg tablet to a maximum of twenty five 100-mg tablets. All patients had methemoglobinemia irrespective of the presence of hemolytic anemia. Among 43 patients, 30 patients (69.8%) were shown to have hemolytic anemia and hemolytic anemia developed the day after admission and persisted for more than 6 days after admission. Even though mortality rate was not sig- nificantly higher in the hemolytic anemia group, the hemolytic anemia group had significantly longer total ad- mission and intensive care unit admission stays than the non-hemolytic group.

Conclusions: A significant proportion of the patients with acute dapsone overdose is associated with occurrence of hemolytic anemia. Hemolytic anemia may be developed the day after admission and persisted for more than 6 days after admission. Therefore, monitoring of serum hemoglobin level is necessary.

(C) 2015

Introduction

Dapsone is a synthetic sulfone that inhibits folate synthesis and was first used in humans in the 1940s to treat leprosy [1]. The adverse effects of dapsone are as follows: chronic adverse effects such as neutropenia, thrombocytopenia, eosinophilic pneumonia, aplastic anemia, hemoly- sis, neuropathy, hepatitis, agranulocytosis, and acute adverse effects such as nausea, vomiting, abdominal pain, methemoglobinemia, sei- zure, and coma [2,3]. Of those, while using dapsone in the therapeutic range, hemolytic anemia has been reported as an adverse event in solid organ transplant recipients receiving dapsone [4,5] and in HIV-infected patients prescribed dapsone to prevent and control Pneumocystis jirovecii [6-9]. Dapsone-induced hemolysis is thought to involve oxygen free radicals through one of the major therapeutically- inactive metabolites, dapsone hydroxylamine, which causes a direct he- molytic effect on the red blood cell [10-12]. However, in acute dapsone overdose, there have been few case reports regarding hemolytic anemia and the incidence and pattern has not been well established [13-15].

* Corresponding author at: Department of Emergency Medicine, Wonju College of Med- icine, Yonsei University, 162 Ilsandong, Wonju, Republic of Korea 220-701. Tel.: +82 33

741 1614; fax: +82 33 742 3030.

E-mail address: [email protected] (H. Kim).

http://dx.doi.org/10.1016/j.ajem.2015.09.021

0735-6757/(C) 2015

Therefore, we retrospectively studied the prevalence and patterns of hemolytic anemia in acute dapsone overdose, and compared prognosis including mortality in the non-hemolytic anemia and the hemolytic anemia groups.

Methods

Study design and data

This is a retrospective and observational study of consecutive patients diagnosed with acute dapsone overdose between January 2006 and January 2014. The emergency department (ED) was located in a single urban, tertiary-care hospital (Wonju Severance Christian Hospital, Wonju, Republic of Korea), which has more than 43,000 annual visits and is staffed 24 hours per day by board-certified emergency physicians.

Poisoning with dapsone was confirmed by patient or guardian state- ments, and verification of drug was performed by an emergency physi- cian who transcribed the drug into patient records. The overdose was defined as ingestion more than a minimum of two 100-mg tablet.

Data were retrospectively collected from medical records and reviewed. Data collection was conducted by two emergency physicians blinded to the Study objectives and hypothesis and if there was inter-

Y.S. Cha et al. / American Journal of Emergency Medicine 34 (2016) 366369

observer disagreement in the interpretation of clinical data, the 2 emer- gency physicians reviewed the case together to come to a conclusion. Training of abstractors was conducted before data collection to reduce bias. The following parameters were assessed: age, gender, possible ingested doses, periods from ingestion to ED arrival, intentionality, gas- tric irrigation, initial symptoms and signs, initial Glasgow Coma Scale (GCS), vital signs, and dose of Methylene blue (methylthioninium chlo- ride). Serum levels of methemoglobin (reference range b 0.5%), and hemoglobin (Hb) were evaluated. Markers of hemolysis including pe- ripheral blood smear (PBS), haptoglobin, Lactate dehydrogenase , indirect bilirubin, and reticulocyte count were investigated. We investigated daily changes in the Hb level. Any complications occurring during the hospitalization and mortality were investigated to compare patient prognosis. Pneumonia was defined as patients with symptoms

367

such as fever, chill, cough, or sputum, and positive image findings such as infiltration, cavity, or abscess, which were confirmed by a radi- ologist. AKI was defined as absolute increase in serum creatinine by >= 0.3 mg/dL from baseline within 48 hr, or increase in serum creatinine to

>= 1.5 times baseline, or urine output of less than 0.5 mL/kg/h for 6 h [16]. neurologic complications were defined as GCS b 13 or seizure dur- ing hospitalization. Shock was defined as systolic blood pressure (SBP) b 90 mmHg.

The criteria for hemolytic anemia are as follows: PBS abnormality

[17] including bite cells, eccentrocytes, schistocytes, and polychromasia with additional abnormal laboratory findings consistent with hemolysis [decreased haptoglobin (reference range, 40-175 mg/dL), elevated LDH (reference range: b 290 U/L), elevated indirect bilirubin (reference range: 0.2-0.7 mg/dL)] as well as a simultaneous decrease in the Hb level. The PBS from all of 43 patients was reviewed and hemolytic anemia was confirmed by two clinical hematologists. If inter-observer disagreement was developed to interpretation of PBS findings,

Fig. 1. Daily hemoglobin changes in the hemolytic anemia group. HD: hospital day.

the final conclusion was made through together review of two clinical hematologists.

When patients have met-Hb concentration greater than 30% or signs and/or symptoms such as hypoxia, cyanosis, altered mental state, sei- zures, ischemic chest pain, electrocardiogram changes, newly devel- oped arrhythmia and/or hypotension, even if met-Hb concentration was lesser than 30%, started use of methylene blue. The protocol for methylene blue administration is to infuse 1 to 2 mg/kg over 10 minutes intravenously at our hospital. If symptoms or methemoglobinemia are persisting, methylene blue administration is repeated. The indication of Packed red blood cells (pRBC) transfusion is profound anemia with impaired oxygen delivery. Although it is difficult to set a transfusion threshold that holds true for all patients, we usually started pRBC trans- fusion when Hb of patient drops to less than 9 g/dL.

Table

General characteristics and comparison of general and laboratory findings according to hemolytic anemia in acute dapsone overdose

Characteristics

Total (n = 43)

Non-hemolytic anemia group (n = 13; 30.2%)

Hemolytic anemia group (n = 30; 69.8%)

P

Age (yrs)

67 (48-79)?

69 (56-79)?

66 (45-79)?

.427

Male gender

13 (30.2%)

5 (38.5%)

8 (26.7%)

.485

Ingestion dose (mg)

600 (400-1000)?

400 (350-600)?

500 (700-1250)?

.006

ED arrival time (hours)

4.0 (2.0-10.0)?

2.5 (0.9-9.5)?

4.0 (3.0-10.5)?

.137

Gastric irrigation

13 (30.2%)

5 (41.7%)

8 (27.6%)

.469

Initial symptoms and signs

Decreased mental state

13 (30.2%)

4 (33.3%)

9 (39.1%)

1.000

Cyanosis

30 (69.8%)

10 (83.3%)

20 (87.0%)

1.000

Dyspnea

25 (58.1%)

8 (66.7%)

17 (73.9%)

.706

Headache

5 (11.6%)

1 (8.3%)

4 (17.4%)

.640

GCS

15 (11-15)?

15 (6-15)?

15 (12-15)?

.824

SBP

140 +- 30+

144 +- 43+

139 +- 25+

.617

Initial Hb (g/dL)

13.0 (12.0-14.3)?

12.9 (12.1-15.0)?

13.1 (11.7-14.4)?

.525

Drop in Hb (g/dL)

4.0 (2.2-6.0)?

2.4 (1.7-3.9)?

4.3 (3.3-6.7)?

.003

Initial methemoglobin (%)

34.4 (26.0-39.2)?

35.5 (28.6-38.9)?

34.4 (24.8-39.6)?

.874

Peak methhemoglobin (%)

34.4 (26.4-40.8)?

35.5 (28.6-38.9)?

34.4 (25.9-41.3)?

.979

Total methylene blue dose (mg)

600 (400-1100)?

450 (600-850)?

400 (800-1225)?

.449

Total transfusion amounts (cc)

1280 (0-3200)?

0 (0-640)?

1840 (780-3740)?

b.001

Haptoglobin (mg/dL)

72.0 (3.5-112.8)?

106.0 (95.0-121.0)?

20.0 (2.0-92.0)?

.026

LDH (U/liter)

515 (275-1243)?

279 (237-563)?

577 (350-1838)?

.016

Indirect bilirubin (mg/dL)

1.5 (0.8-2.5)?

0.8 (0.5-1.1)?

1.8 (1.2-3.2)?

.001

Reticulocyte count (E9/L)

61.3 (31.0-92.7)?

57.7 (45.2-72.9)?

64.3 (25.1-99.4)?

.906

Complications

Pneumonia

22 (51.2%)

4 (30.8%)

18 (60.0%)

.078

Acute kidney injury

12 (27.9%)

2 (15.4%)

10 (33.3%)

.290

Neurologic complications

9 (20.9%)

2 (15.4%)

7 (23.3%)

.699

Shock

12 (27.9%)

3 (23.1%)

9 (30.0%)

.727

Outcome

Total admission days

8 (5-16)?

5 (3-7)?

13 (7-16)?

.003

ICU admission days

3 (0-10)?

0 (0-5)?

4 (1-16)?

.022

Mortality

10 (23.3%)

2 (15.4%)

8 (26.7%)

.696

ICU, intensive care unit

* Median (interquartile range).

+ Mean +- SD.

368 Y.S. Cha et al. / American Journal of Emergency Medicine 34 (2016) 366369

(1 patient), gastrointestinal bleeding during admission (2 patients), the absence of a PBS (3 patients), and poisoning with any additional ma- terial including sedatives (3 patients).

There were 13 male patients (30.2%) and the ages of all patients ranged from 18 to 93 years with a median of 67 years. In all cases dap- sone was ingested intentionally. The ingested dose varied from a mini- mum of two 100-mg tablet to a maximum of 25 100-mg tablets and ingested dose of the hemolytic anemia group was significantly higher than that of the non-hemolytic anemia group (P = .006). The most com- mon symptoms and signs at initial presentation included cyanosis (30 patients, 69.8%), dyspnea (25 patients, 58.1%), decreased mental state (13 patients, 30.2%), and headache (5 patients, 11.6%). Other symptoms included nausea, vomiting, general weakness, dizziness, and seizures. Age, periods from ingestion to ED arrival, gastric irrigation, initial symp- toms and signs, initial GCS, and SBP were not significantly different be-

tween the non-hemolytic anemia and hemolytic anemia groups (Table).

Fig. 2. Comparison of daily changes of methemoglobin between the non-hemolytic ane- mia and hemolytic anemia groups. HD: hospital day.

Exclusion criteria were age below 18 years old, gastrointestinal bleeding during admission (with endoscopy confirmation), absence of PBS results, and patient’s medical history of hematologic disease includ- ing hemolytic anemia and poisoning with any additional material ex- cept for alcohol on the basis of history.

This study was approved by the institutional review board commit- tee of Wonju College of Medicine, Yonsei University.

Statistical analysis

Categorical variables are presented as frequencies and percentages, and continuous variables are presented as mean and SD, or median and IQR after investigating for normality using the Shapiro-Wilk test. ?2 Test or Fisher exact test were used for comparison of categorical var- iables while the 2-sample t test and Mann-Whitney U test were used for continuous variables. We measured repeated met-Hb, methylene blue dose, and Hb and analyzed the variables using a mixed model. P b.05 was considered statistically significant. Statistical analyses were per- formed using SAS 9.2 Ver. (SAS Institute Inc, Cary, NC) and SPSS Ver. 20 (IBM, Aramark, NY).

Results

A total of 43 consecutive patients were determined to be eligible for this study while 9 patients were excluded from the study due to the fol- lowing exclusion criteria: previous hematologic disease history

Fig. 3. Comparison of daily changes of methylene blue between the non-hemolytic anemia and hemolytic anemia groups with acute dapsone poisoning. HD: hospital day.

In this study, the mean time of the examined PBS was 2.3 days. Re- view of the PBS and additional laboratory data revealed that hemolytic anemia occurred in 30 patients (69.8%) out of total 43 patients. In the hemolytic anemia group, the median drop in hemoglobin from baseline was 4.3 g/dL and drops in Hb from baseline developed the day after ad- mission and persisted for more than 6 days after admission (Fig. 1). De- creases of median haptoglobin, elevation of median LDH, and elevation of median indirect bilirubin were 20.0 mg/dL, 577 U/L, and 1.8 mg/dL in hemolytic anemia group, respectively. Additionally, drops in Hb, hapto- globin, LDH, and indirect bilirubin were statistically different between the two groups (Table).

All patients had methemoglobinemia irrespective of the presence of hemolytic anemia. The median value of the initial methemoglobin level was 34.4% and there was no statistically significant difference (Table). Compared to daily met-Hb patterns, there was no significant difference between the non-hemolytic anemia and hemolytic anemia groups (P =

.834) (Fig. 2).

There was no significantly different irrespective of total methylene blue dose used (P = .449) and daily pattern of methylene blue dosage between the non-hemolytic anemia and hemolytic anemia groups (P = .590) (Table and Fig. 3).

The most common complication after acute dapsone overdose was pneumonia (22 patients, 51.2%). While there were generally more com- plications in the hemolytic anemia group there were no statistical dif- ferences between the two groups. However, total admission and intensive care unit admission lengths were statistically longer in the hemolytic anemia group than the non-hemolytic anemia group. Al- though a total of 10 patients (23.3%) died from pneumonia and multi- system organ failure, there was no significant difference of mortality ac- cording to presence of hemolytic anemia (Table).

Discussion

In this study, the prevalence of hemolytic anemia in acute dapsone overdose was 69.8%. To my best knowledge, these results are novel as no previous investigation has been conducted on hemolytic anemia oc- currence after an acute dapsone overdose. Naik et al [4] reported hemo- lytic anemia while using dapsone in the therapeutic range was occurred in 10 patients (22.7%) out of all 43 patients. Therefore, we also found that prevalence of hemolytic anemia was higher in acute overdose than in the use of Therapeutic dose.

In our study, drops in Hb from baseline developed the day after ad- mission and persisted for more than 6 days after admission (Fig. 1). Over- all, Hb levels were temporarily elevated at 7 day but decreased again at 8 day in the hemolytic anemia group. We think that temporary elevation of Hb at 7 day may be due to pRBC transfusion because just as we have mentioned above we usually started pRBC transfusion when Hb of pa- tient drop to less than 9 g/dL. We thought that reasons for the high prev- alence and long duration of hemolytic anemia were due to the elimination half-life of dapsone of approximately 30 hours, long lasting

Declaration of interest“>Y.S. Cha et al. / American Journal of Emergency Medicine 34 (2016) 366369 369

of methemoglobinemia by having longer elimination half-life of dapsone, which caused more methylene blue used. Methylene blue, alone, can in- duce an acute hemolytic anemia independent of the presence of methe- moglobinemia [18-20]. However, there was no significant difference in total methylene blue dose (p = 0.449) and daily pattern of use of meth- ylene blue (P = .590). This indicates that methylene blue did not cause the difference in the developing hemolytic anemia in this study.

Based on the results obtained, physicians should remember that he- molytic anemia occurs frequently and hemolytic anemia needs to be ad- ditionally evaluated at the time of initial work-up in acute dapsone overdose. In this study, a median pRBC transfusion to treat hemolytic anemia in patients with acute dapsone overdose was 1840 cc. However, because the indication of PRBC transfusion might vary among hospitals and countries, amounts of transfusion may be also different.

Generally, duration of treatment in dapsone poisoning is longer than treatment of methemoglobinemia developed by other causes because of a long elimination half-life. Even though mortality rate was not signifi- cantly higher in the hemolytic anemia group, the hemolytic anemia group had significantly longer total admission and ICU admission stays than the non-hemolytic group. Therefore, if the patient has hemolytic anemia during treatment, the duration of hospitalization may be longer in patients with hemolytic anemia.

In this study, ingested dose was higher in the hemolytic anemia group. Therefore, when a patient has ingested large amounts of dapsone with suicidal intent, clinicians should keep in mind that hemolytic ane- mia is more likely to occur. This study did not show a difference in age between the non-hemolytic anemia and hemolytic anemia groups al- though we thought hemolytic anemia would happen more frequently in the older patients due to lack of physiological functional reserve.

We aggressively have usED treatments including gastric irrigation, acti- vated charcoal, and repeated use of methylene blue if met-Hb level did not drop despite the use of methylene blue through consensus of experienced doctors for acute dapsone overdose because mortality of acute dapsone overdose was high (23.3%). Therefore, we thought that incidence of gastric irrigation and total methylene blue dose may be higher.

This study had some limitations. It was a retrospective study and involved only one hospital. As a result, not all relevant assessment parameters could be included. The ingested amount of toxin, the ED ar- rival time after ingestion, and initial symptoms and signs may be overestimated or underestimated. Second, we did not check the PBS of 3 patients in all acute dapsone overdose patients and therefore, selec- tion bias may have occurred. Third, if Repeat examinations are done con- tinuously for laboratory tests related to hemolytic anemia, including PBS, haptoglobin, LDH, indirect bilirubin, and reticulocyte count, the du- ration of hemolytic anemia will be understood more precisely. Fourth, we did not measure glucose-6-phosphate dehydrogenase (G-6-PD) levels in our study. G-6-PD deficiency patients have been excluded from most Treatment protocols because methylene blue is a mild oxi- dant and case reports have suggested methylene blue toxicity. Howev- er, because of the lack of immediate availability of G-6-PD testing, most patients who need treatment receive Methylene blue therapy before their G-6-PD status is known [21] and unfortunately, there was no re- port of incidence of G-6-PD in Korea. Fifth, due to long elimination half-life of dapsone, repeated methylene blue were used in acute dap- sone poisoning. Although we could not precisely know the effect of he- molysis by use of methylene blue, we presented that there was no significant difference in total methylene blue dose (P = .449) and daily pattern of use of methylene blue (P = .590) between the non- hemolytic anemia and hemolytic anemia groups. Sixth, we did not check serum dapsone level due to the absence of apparatus. Therefore,

we could not investigate relations between serum dapsone level and hemolysis. However, few hospitals have machine to determine the serum concentration of dapsone. To overcome the limitations, further prospective study will be needed.

Conclusions

Significant proportion of the patients with acute dapsone overdose is associated with occurrence of hemolytic anemia. Hemolytic anemia may develop the day after admission and continue for more than 6 days after admission. Therefore, monitoring of serum hemoglobin level is necessary.

Declaration of interest

The authors have no potential conflict of interest to declare.

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