|Year : 2015 | Volume
| Issue : 4 | Page : 491-498
Use of pentoxifylline for patients in the postcardiac arrest status
Noha M Elsharnouby MD, MBBCH 1, Nahla F Abou Elezz2
1 Department of Anesthesia and Intensive Care, Faculty of Medicine, Ain Shams University, Cairo 11361, Egypt
2 Department of Community, Environmental and Occupational Medicine, Faculty of Medicine, Ain Shams University, Cairo 11361, Egypt
|Date of Submission||02-Dec-2013|
|Date of Acceptance||28-Dec-2013|
|Date of Web Publication||29-Dec-2015|
Noha M Elsharnouby
3 Ismail Fahmy Street, Seven Building Square, Heliopolise, Cairo
Source of Support: None, Conflict of Interest: None
Postcardiac arrest syndrome has a unique pathophysiological process involving multiple organs. Pentoxifylline can modulate inflammation, oxidative stress, and endothelial function, and may thus reduce multiple organ dysfunction in postcardiac arrest patients and affect the outcome. The aim of this study was to evaluate the effect of intravenous pentoxifylline on organ functions and outcome in postcardiac arrest patients.
Materials and methods
Forty-two patients admitted to the ICU after inhospital cardiac arrest of both cardiac and noncardiac origin were included in this prospective double-blinded randomized two parallel-group study. Group P received a first dose of intravenous pentoxifylline 5 mg/kg over 5 min, followed by a 1.5 mg/kg/day infusion with a maximum of 1800 mg/day for 3 days, whereas group C received an equal volume of saline over 5 min and then infusion for 3 days as well. The primary outcome was the number of organ dysfunction-free and organ failure-free days, whereas the secondary outcome included time to initial acceptable blood pressure and systemic perfusion, number of acceptable blood pressure and systemic perfusion days, arterial lactate, Cerebral Performance Category score, duration of inotropic support, duration of mechanical ventilation, length of ICU stay, ICU survival, and adverse events.
There was a significant increase in the number of organ dysfunction-free days [9 (3) vs. 6 (3), P = 0.003] and organ failure-free days [9 (3) vs. 7 (3), P = 0.008], accompanied by an increased number of acceptable blood pressure and systemic perfusion days [8 (3) vs. 6 (4), P = 0.01], with a shorter time to reach initial acceptable blood pressure and systemic perfusion [68 (51) vs. 38 (36), P = 0.03 ] and a significant improvement in the Cerebral Performance Category score on days 6, 7, and 14 in group P compared with group C. The arterial lactate level, duration of mechanical ventilation, duration of inotropic support, and ICU length of stay were significantly reduced in group P, along with an improvement in ICU survival that did not reach statistical significance.
We conclude that administration of intravenous pentoxifylline in postcardiac arrest patients improved organ function and decreased length of ICU stay, with no adverse effects.
Keywords: ICU length of stay, pentoxifylline, postcardiac arrest, sequential organ failure assessment score, survival
|How to cite this article:|
Elsharnouby NM, Abou Elezz NF. Use of pentoxifylline for patients in the postcardiac arrest status. Ain-Shams J Anaesthesiol 2015;8:491-8
|How to cite this URL:|
Elsharnouby NM, Abou Elezz NF. Use of pentoxifylline for patients in the postcardiac arrest status. Ain-Shams J Anaesthesiol [serial online] 2015 [cited 2020 Apr 9];8:491-8. Available from: http://www.asja.eg.net/text.asp?2015/8/4/491/172669
| Introduction|| |
Despite advances in cardiac arrest resuscitation, the mortality rates remain considerably high and can be attributed to postcardiac arrest syndrome with the unique pathophysiological process involving multiple organs  . Ischemia/reperfusion and nonspecific activation of the inflammatory response are believed to contribute toward cellular abnormalities and multiorgan dysfunction  . Recent research proved that the outcome is determined by both the time to circulation recovery and the pathogenic processes that are triggered by the cardiac arrest, which continue to evolve subsequently, causing damage to the nervous system and other organs , . Clinical research confirmed the beneficial effect of therapeutic hypothermia in improving the outcome , . Finding new targets for additional therapeutic interventions that can improve the outcome is a high priority for resuscitation research.
Pentoxifylline is a methylxanthine derivative that functions as a phosphodiesterase inhibitor and can modulate inflammation, oxidative stress, and endothelial function  . Pentoxifylline inhibits proinflammatory cytokines such as tumor necrosis factor-a, interleukin-10  , and interleukin-1  . Also, pentoxifylline inhibits xanthine oxidase activity, which is a source of free oxygen radicals in the ischemic reperfusion injury  . Several previous studies have been carried out on the beneficial effect of pentoxifylline in sepsis  , perforation peritonitis  , meningitis  , and acute respiratory distress syndrome (ARDS)  , and also in alleviating inflammatory response , and reducing acute kidney injury after cardiac surgery  .
The aim of this study was to evaluate the effect of intravenous pentoxifylline on organ functions and outcome in postcardiac arrest patients.
| Materials and methods|| |
After the protocol was approved by our institution medical board and after return of spontaneous circulation (ROSC) after inhospital cardiac arrest and transfer of patients to the ICU, patients' guardian or next of kin provided informed written consent. Forty-two patients fulfilled the inclusion criteria: age above 18 years old, of both sexes, inhospital cardiac arrest, both cardiac and noncardiac origin, delay between collapse and onset of cardiopulmonary resuscitation less than 10 min, time from cardiac arrest to ROSC less than 30 min, and glasgow coma score (GCS) less than 8 after ROSC.
Exclusion criteria included out-of-hospital cardiac arrest, previous or current treatment with pentoxifylline, methylxanthine derivatives, amrinone, NSAIDs, coagulopathy, intracranial hemorrhage, thrombocytopenia (platelet count<50 000/mm 3 ), cardiac arrest because of trauma and traumatic brain injury, pregnancy, terminal moribund disease, ROSC in more than 30 min, cardiac arrest secondary to drowning or hanging, and severe hypothermia (<30°C).
After an emergency call of the advanced life support (ALS) team, the ALS team continued chest compression and placed an endotracheal tube (verifying the proper position using a capnography) and initiated cardiopulmonary resuscitation according to the latest guidelines (the International Liaison Committee on Resuscitation - European Resuscitation Council)  using the ALS algorithm for both shockable and nonshockable rhythm. End-tidal PCO 2 (PETCO 2 ) was measured to estimate the hemodynamic efficacy of chest compression.
After ROSC, standard postresuscitation care was performed, patients were transferred to the ICU, and assigned randomly using a computerized program in this randomized prospective double-blinded study to one of the two parallel groups (Group C n = 21 patients and 21 patients in Group P) during a 1-year study period from March 2012 to March 2013. Patients were assigned randomly to two groups after admission to the ICU by opening sequentially numbered opaque envelopes. Group P received a first dose of intravenous pentoxifylline 5 mg/kg over 5 min, followed by a 1.5 mg/kg/day infusion, with a maximum of 1800 mg/day for 3 days, whereas group C received an equal volume of saline over 5 min and then infusion for 3 days as well.
Data were collected according to the Utstein style for reporting cardiac arrest research recommended for postresuscitation research  . In the ICU, all patients were monitored and received the standard protocol of intensive Care Unit management in Ain Shams University Hospital for postcardiac arrest including induced hypothermia using an adjusted dose of sedative (midazolam and fentanyl) and cooling to a core temperature between 32 and 34C by external means until they regained consciousness or had completed 24 h, and then slowly progressively rewarmed, followed by intravenous fluids resuscitation, maintenance of electrolyte and glucose level within normal ranges, administration of antimicrobials, stress ulcer prophylaxis (proton pump inhibitor), enteral nutrition, and administration of analgesics, antipyretics, and prophylactic low-molecular-weight heparin. Patients with ST-segment elevation myocardial infarction received percutaneous coronary interventions. Inotropic and vasopressor agents were infused guided by hemodynamic monitoring using central venous pressure monitoring to achieve hemodynamic goals targeted at a mean arterial blood pressure of more than 65 mmHg and good organ perfusion using arterial lactate measurements and urine output (UOP).
The ICU team included intensive care physicians and nursing staff who were unaware of the study medication. Data recorded included patients' characteristics, clinical characteristics [initial heart rhythm, age, sex, BMI, time to start CPR (no-flow duration), etiology of cardiac arrest, duration of cardiopulmonary resuscitation (low-flow duration)], severity assessed by the simplified acute physiology score II (SAPS II)  score, and sequential organ failure assessment (SOFA)  score, neurological performance, arterial lactate level, and postresuscitation shock.
Neurological performance was assessed and recorded on admission, and on days 1, 2, 3, 4, 5, 6, 7, and 14 or before patient discharge from the ICU using the Glasgow-Pittsburgh Cerebral Performance Category (CPC) scale [Table 1]  . In case of ICU death before day 14, CPC were considered level 5. By day 14, patients with CPC 1 and 2 were considered to have a good neurological outcome, whereas those with CPC 3, 4, and 5 were considered to have a poor outcome.
Postresuscitation shock was defined as sustained (>4 h), new postarrest circulatory failure or postarrest need for a 50% or greater increase in any prearrest vasopressor/inotropic support targeted to a mean arterial pressure greater than 70 mmHg  .
During the study period, careful neurological and cardiac examinations were performed daily for all patients. Routine ECG, continuous invasive blood pressure, SPO 2 , and hourly central venous pressure (CVP) and UOP were recorded. Twice-daily assessment of central venous blood gas sampling for monitoring central venous oxygen saturation (ScvO 2 ) as well as daily assessment renal function (UOP and serum creatinine), liver function test [alanine transaminase (ALT) and aspartate transaminase (AST)], and platelet count were performed.
Organ dysfunction and organ failure were defined by SOFA above one and above two, respectively, and the need for inotropic support was recorded. Organ failure or dysfunction-free days were defined as the number of days between ICU admission (day 1) and day 14 with the patient alive without any organ failure. In case of ICU death before day 14, organ failure-free days were considered equal to zero. Patients discharged from ICU before day 14 were considered free from organ failure after ICU discharge. SOFA scores were calculated using the worst value for each component daily.
The time to reach acceptable blood pressure and systemic perfusion (ABPSP) and the acceptable blood pressure and systemic perfusion days (ABPSPD) were recorded during the 14-day study period. ABPSPD was defined as a mean arterial pressure of at least 65 mmHg, UOP greater than 1 ml/kg/h, and ScvO 2 at least 70%, with no increase in the infusion of vasopressors or inotropic therapy maintained for 4 h. All patients were mechanically ventilated and weaned from mechanical ventilation upon improvement according to protocols.
Any suspected adverse events of pentoxifylline were assessed and recorded as bleeding, leukopenia (<4.0 × 10 9 /l), thrombocytopenia (platelet count less than 150 ΄ 10 9 /l), cardiovascular disturbances (episodes of arrhythmia), jaundice (total and direct bilirubin more than two times the upper normal limit) and increased liver enzymes (ALT and AST more than two times the upper normal limit), and GIT symptoms (episodes of nausea and vomiting). The safety of pentoxifylline was evaluated during the study period and pentoxifylline therapy was stopped if the patient developed adverse events: length of ICU stay and ICU survival were recorded during the study period.
The primary outcome was the number of organ dysfunction-free days and organ failure-free days as assessed by the SOFA score up to day 14, whereas the secondary outcome included time to initial ABPSP, number of ABPSPD, arterial lactate, neurological outcome as assessed by CPC score, duration of inotropic support (dopamine, dobutamine, epinephrine, and norepinephrine), duration of mechanical ventilation, length of ICU stay, ICU survival, and adverse events.
A sample size of 38 patients (19 patients per group) was estimated at a power of study = 80% and a = 0.05 using Power and Sample size calculation. A pilot study of 10 patients was carried out and a sample size of 19 patients per group was sufficient to detect a 20% difference with a 1.68 SD in organ failure or dysfunction-free days assessed by the SOFA score. A total of 10% was added to the sample to cover for possible dropouts.
Statistical analysis was carried out using the SPSS version 15.0 package (SPSS Inc., Chicago, Illinois, USA). Data were expressed as mean (SD) for quantitative parametric measures and comparison was performed using an independent t-test. Categorical data were expressed as both number and percentage and compared using the c2 -test or the exact Fisher test. Quantitative variables are reported as median and compared using the nonparametric Mann-Whitney test. A P value less than 0.05 was considered significant. Logistic regression analysis was carried out to adjust for other covariates that may affect the outcome such as patients' characteristics, CPR characteristics, and admission characteristics (age and BMI, on admission arterial lactate level, time to start CPR, CPR duration SAPS II score, SOFA score, CPC score on admission, sex, hospital cause of admission, etiology of cardiac arrest, initial rhythm of cardiac arrest, postresuscitation shock, and percutaneous coronary intervention). Kaplan-Meier analysis was carried out for ICU survival during the 14-day length of ICU stay.
| Results|| |
Fifty-four patients were admitted to ICU following cardiac arrest; three patients had a moribund disease, two patients had coagulopathy, two patients had intracerebral hemorrhage, and we were unable to obtain consent in five cases. The study group included 42 patients; the majority were men, 62%, mean age 55 (15) years, with BMI 26 (4) (kg/m 2 ), mean time to CPR 4 (3) min, duration of CPR 12 (6) min, median SAPS II score 60, and SOFA score of 9.59% because of cardiac arrest of cardiac origin. A percutaneous coronary intervention was performed in 9 (21%) cases. All were similarly treated with induced hypothermia during the first 24 h. There was no significant difference between the groups in the patients' characteristics, SAPS II score, SOFA score, CPR characteristics, cause of admission to hospital, admission arterial lactate level, CPC, and postresuscitation shock as well as patients undergoing a percutaneous coronary intervention [Table 2]. Logistic regression analysis was carried out to adjust for other covariates that may affect the outcome [Table 3].
|Table 2 Patients' characteristics, CPR characteristics, and admission characteristics|
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|Table 3 Logistic regression analysis was carried out to adjust for other covariates that may affect the outcome|
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During ICU stay, there was a significant increase in the number of organ dysfunction-free days (P = 0.003) and organ failure-free days (P = 0.008) as assessed by the SOFA score up to day 14; this was accompanied by an increase in the number of ABPSPD (P = 0.01), with a shorter time to reach initial ABPSP (P = 0.03) in group P than in group C. The arterial lactate level (P = 0.01), duration of mechanical ventilation (P = 0.04), and duration of inotropic support (P = 0.02) were also significantly decreased in group P compared with group C [Table 4]. The CPC score was significantly improved on days 6, 7, and 14, but was nonsignificantly different on days 1, 2, 3, 4, and 5 [Table 5].
|Table 4 Outcome parameters: mean (SD) for organ dysfunctionfree days, organ failure-free days, number of ABPSPD, time to reach initial ABPSP, arterial lactate level, duration of mechanical ventilation, duration of inotropic support, length of ICU stay|
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|Table 5 CPC score: median (mean rank) for CPC score on days 1, 2, 3, 4, 5, 6, 7, and 14|
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In the study group, the mean (SD) of the number of organ dysfunction-free days was significantly increased (P = 0.0001) in survivors 10 (3) than nonsurvivors 6 (3), with a significantly increased (P = 0.0001) mean (SD) of the number of organ failure-free days in survivors 11 (2) than nonsurvivors 7 (2).
In group C, there was a significant increase in both the number of organ dysfunction-free days (P = 0.02) and organ failure-free days (P = 0.0001) in survivors than nonsurvivors. Also, in group P, the number of organ dysfunction-free days (P = 0.004) and organ failure-free days (P = 0.0001) were significantly increased among survivors compared with nonsurvivors [Figure 1] and [Figure 2].
|Figure 1: Boxplot showing organ dysfunction-free days [mean (SD)] in both survivors and nonsurvivors in the study groups. Group C = control group and group P = pentoxifylline group. Organ dysfunction was defined by a sequential organ failure assessment (SOFA) score above one for the appropriate function.*P < 0.05 indicates a significant difference between group s|
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|Figure 2: Boxplot showing organ failure-free days [mean (SD)] in both survivors and nonsurvivors in the study groups. Group C = control group and group P = pentoxifylline group. Organ dysfunction was defined by a sequential organ failure assessment (SOFA) score above two for the appropriate function. *P < 0.05 indicates a significant difference between groups. |
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There was a significant reduction (P = 0.03) in ICU length of stay, along with an improvement in ICU survival in group P compared with group C; however, ICU survival (P = 0.5) did not reach statistical significance [Table 4]. Kaplan-Meier analysis was carried out for ICU survival during the 14-day length of ICU stay [Figure 3].
|Figure 3: Kaplan– Meier survival analysis. Group C = control group and group P = pentoxifylline group|
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On discharge, patients with CPC scores 1 and 2 were considered to have a good neurological outcome, whereas those with CPC scores 3, 4, and 5 were considered to have a poor outcome. All 13 patients who survived had a good outcome, whereas eight patients who had a good outcome were nonsurvivors and 21 patients with a poor outcome were also nonsurvivors. Neurological outcome was significantly related to survival (P = 0.0001) [Figure 4].
|Figure 4: Bar charts showing neurological outcome (number of patients) in survivors and nonsurvivors. Neurological outcome was assessed by the CPC score. Patients with CPC scores 1 and 2 were considered to have a good neurological outcome, whereas those with CPC scores 3, 4, and 5 were considered to have a poor outcome.*P<0.05 indicates a significant difference between groups|
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Administration of pentoxifylline in postcardiac arrest patients was safe as there was no bleeding, leukopenia, thrombocytopenia, cardiovascular disturbances, jaundice, and increase in liver enzymes (ALT and AST) and GIT symptoms (nausea and vomiting) reported during pentoxifylline infusion.
| Discussion|| |
In this study, we investigated the effect of administration of intravenous pentoxifylline 5 mg/kg over 5 min, followed by a 1.5 mg/kg/day infusion with a maximum of 1800 mg/day for 3 days for postcardiac arrest patients. There was an increase in the number of organ dysfunction-free days and organ failure-free days as assessed by the SOFA score up to day 14.
The use of pentoxifylline was accompanied by increased numbers of ABPSPD, with a shorter time to reach initial ABPSP and reduced arterial lactate level, duration of mechanical ventilation, duration of inotropic support, and ICU length of stay, with an improvement in ICU survival that did not reach statistical significance.
Postcardiac arrest ischemia/reperfusion injury has been shown to activate immunologic and coagulation pathways leading to an increased risk of multiple organ dysfunction ,, , and thus produced a sepsis-like state, resulting in a profound inflammatory response evidenced by marked increases in cytokine production, presence of plasma endotoxin  , and impaired microcirculatory blood flow  . Thus, measures to attenuate multiple organ dysfunctions may improve clinical outcomes.
In the current study, we used the SOFA score  , which is a simple and objective scoring system that quantifies the severity of organ dysfunction in six organ systems (respiratory, coagulation, hepatic, renal, cardiovascular, and neurological) and has been validated as a predictor of morbidity and mortality in critically ill patients ,, . In our study, the neurological status was assessed using the Glasgow-Pittsburgh CPC scale, which is commonly used in the postarrest setting , . We also collected data in accordance with the Utstein style to report cardiac arrest research recommended for postresuscitation research to ensure uniform reporting on inhospital cardiopulmonary resuscitation  and used logistic regression analysis to adjust for other covariates that affect the outcome.
Various therapeutic interventions have been investigated in the postcardiac arrest period in an attempt to improve survival. A study using coenzyme Q10 reported improvements in both survival and neurological outcome  . Another study was carried out using high doses of Epo-alpha and found a high survival rate, with minimal cerebral sequels, but potential hematological side effects  .
In an attempt to reduce postcardiac arrest multiorgan dysfunction, we chose to use intravenous pentoxifylline in postcardiac patients. Pentoxifylline was a phosphodiesterase enzyme inhibitor, with an antioxidant, anti-inflammatory , , and anticoagulation effect that led to improved red blood cell deformability, decreased red blood cell aggregation, inhibition of neutrophil adhesion  , and beneficial effects in treating liver fibrosis and cirrhosis through its antifibrogenic action , . In addition, pentoxifylline was found to exert beneficial effects in cerebrovascular disease by inhibiting brain edema, reducing disturbances in brain cell membrane permeability, removing mechanical obstacles in microcirculation, and also increasing global and regional cerebral blood flow , . Miller et al.  reported a maximum plasma concentration of pentoxifylline within 5 min following its injection.
In our study on the use of pentoxifylline, the CPC score was significantly improved on days 6, 7, and 14, and the neurological outcome was significantly improved in the survival group as all 13 patients who survived had a good outcome. The number of organ dysfunction-free and organ failure-free days were significantly higher in survivors than nonsurvivors in the entire study group, with an increase in the number of organ dysfunction-free and organ failure-free days in the survivors than nonsurvivors in group P and group C. In our study, the use of pentoxifylline was accompanied by improvements in the neurological outcome as well as organ function as assessed by the SOFA score and a shorter length of ICU stay. Although ICU survival was increased in the pentoxifylline group [7 (33%)] compared with the control group [5 (24%)], it did not reach statistical significance. This might have been because of the small sample size in the study group and ICU survival.
Previous studies have reported survival to hospital discharge to range from 0 to 42%, with the most common range being between 15 and 20%  ; however, in this study, we used ICU survival discharge, which might explain the slightly increased survival discharge than the most commonly reported range.
In agreement with our study, previous studies have been carried out using pentoxifylline after cardiac surgery and showed reduced levels of inflammatory factors and duration of mechanical ventilation, along with better outcome in the pentoxifylline group , . Barkhordari et al.  reported that pentoxifylline reduced the occurrence of AKI after cardiac surgery as determined by attenuation of increase in serum creatinine without causing hemodynamic instability or increased bleeding.
Sliwa et al.  hypothesized that the inhibition of phosphodiesterase activity by pentoxifylline led to an improvement in LVEF through an increase in intracellular cyclic adenosine monophosphate and decrease in tumor necrosis factor-a. In agreement with this, Skudicky et al.  suspected that an inhibition of apoptosis by pentoxifylline was responsible for its beneficial effects on LVEF. The beneficial effect of pentoxifylline on left ventricular ejection fraction might have caused the increased number of ABPSPD with a reduced time to reach initial ABPSP, arterial lactate, and duration of inotropic support associated with improved organ function as assessed by the SOFA score, causing the increased number of organ dysfunction-free and organ failure-free days in group P compared with group C.
Administration of pentoxifylline in postcardiac arrest patients was safe as no bleeding, leukopenia, thrombocytopenia, cardiovascular disturbances, jaundice, and increase in liver enzymes (ALT and AST) and GIT symptoms (nausea and vomiting) were reported during pentoxifylline infusion.
The current study has potential limitations; it is a small study based on a single center, was of a short duration, and survival was limited to ICU survival. This study also did not perform measurements of pentoxifylline levels during the study period. However, we are not aware of randomized-controlled trials that have used intravenous pentoxifylline in postcardiac arrest patients. Further studies are thus warranted on the effect of pentoxifylline in postcardiac patients with a longer study period considering hospital survival discharge as well as posthospital survival along with measurement of pentoxifylline levels in an attempt to determine the optimum dose and duration of intravenous pentoxifylline in postcardiac arrest patients.
We conclude that administration of intravenous pentoxifylline in postcardiac arrest patients improved organ function and decreased length of ICU stay, with no adverse effects.
| Acknowledgements|| |
Financial support was provided by institution resources only.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]