|Year : 2016 | Volume
| Issue : 2 | Page : 219-224
Effect of alpha-lipoic acid on acute lung injury and acute kidney injury in major postpartum hemorrhage
Rania M Ali MD 1, Marwa A Khairy1, Dina Y Mansour2
1 Department of Anesthesiology and Intensive Care, Ain-Shams University, Cairo, Egypt
2 Department of Obstetrics and Gynecology, Ain-Shams University, Cairo, Egypt
|Date of Submission||27-Apr-2015|
|Date of Acceptance||13-May-2015|
|Date of Web Publication||11-May-2016|
Rania M Ali
Department of Anesthesiology and Intensive Care, Ain-Shams University, Cairo
Source of Support: None, Conflict of Interest: None
Postpartum hemorrhage (PPH) is a major cause of maternal morbidity and mortality. Resuscitated hemorrhagic shock patients are susceptible to the development of a systemic inflammatory response and organ dysfunction. This study aimed to investigate the effects of alpha-lipoic acid (ALA) as an adjunctive therapy that protects against the occurrence of acute lung injury (ALI) and acute kidney injury (AKI) in patients with major PPH.
Patients and methods
Forty patients admitted to Ain Shams Obstetric ICU with major PPH were randomly allocated into two equal groups: the ALA group received intravenous 1200 mg ALA once daily for 3 days and the placebo group received 500 ml of 0.9% isotone saline solution over 60 min once daily for 3 days. The primary study outcome was the serum levels of thiobarbituric acid reactive species as a marker of oxidative damage and interleukin-6 as a marker of inflammatory response. The secondary outcomes were the incidence of ALI and AKI.
ALA attenuated the oxidative damage and the inflammatory response as evidenced by the reduction in both thiobarbituric acid reactive species and interleukin-6 levels, respectively (P < 0.001). AKI developed in 5% of patients in the ALA group versus 25% of patients in the placebo group 48 h after ICU admission. The oxygenation index (PaO 2 /FiO 2 ) reached less than 300 in 10% of patients in the ALA group and in 30% of patients in the placebo group.
ALA decreases markers of oxidative stress and inflammatory response and also has a preventive effect on the progression of ALI and AKI in patients with major PPH.
Keywords: acute kidney injury, acute lung injury, alpha-lipoic acid, postpartum hemorrhage
|How to cite this article:|
Ali RM, Khairy MA, Mansour DY. Effect of alpha-lipoic acid on acute lung injury and acute kidney injury in major postpartum hemorrhage. Ain-Shams J Anaesthesiol 2016;9:219-24
|How to cite this URL:|
Ali RM, Khairy MA, Mansour DY. Effect of alpha-lipoic acid on acute lung injury and acute kidney injury in major postpartum hemorrhage. Ain-Shams J Anaesthesiol [serial online] 2016 [cited 2021 Apr 19];9:219-24. Available from: http://www.asja.eg.net/text.asp?2016/9/2/219/182261
| Introduction|| |
Postpartum hemorrhage (PPH) is one of the most common causes of maternal morbidity and mortality worldwide. Most deaths resulting from PPH occur during the first 24 h after birth .
Ischemia/reperfusion (I/R) injury is a potent trigger of the inflammatory process, as it results in a burst of reactive oxygen species (ROS) into the circulation . Prompt resuscitative measures such as speedy bleeding control, fluid resuscitation, and cause-directed management are fundamental to restore tissue perfusion and oxygenation . However, these life-saving procedures can be regarded as the major contributing factors to global I/R injury and, eventually, compromise vital organs [4,5].
The lungs are among the earliest and most frequently affected organs . The mechanism by which I/R modulates immunity, leading to exacerbated pulmonary response, is not completely known, but studies show that acute lung injury (ALI) occurs after reperfusion, with fast generation of ROS and cytokines .
Acute kidney injury (AKI) is a common complication following major hemorrhage and it has been shown to be an independent factor associated with mortality in critically ill patients . Even when systemic vital parameters are restored by fluid resuscitation and blood transfusion, tissue oxygenation in the kidney remains inadequate due to disturbed microvascular regulatory mechanisms as a result of systemic inflammation and oxidative stress associated with hemorrhagic shock .
It has been demonstrated that antioxidant agents, when administered during resuscitation, protect against tissue damage in experimental models of hemorrhagic shock by reducing oxidative stress and attenuating inflammatory response, thereby protecting against ALI and AKI [6,10].
Alpha-lipoic acid (a-lipoic acid, ALA), also termed 'a universal antioxidant', is a disulfide derivative of octanoic acid. It is considered as a cofactor in mitochondrial multienzyme complexes in the cascade of energy production. ALA has antioxidant properties such as regeneration of endogenous antioxidants, increased formation of glutathione (GSH), and neutralization of free oxygen radicals .
It has been shown that ALA attenuated I/R injury  and protected against warm ischemia . Moreover, it has been shown that ALA attenuates hemorrhagic-shock-induced apoptotic signaling and vascular hyperpermeability in experimental models .
The kidney and lungs are the major target organs in hemorrhagic shock; however, effective prevention of I/R injury has not yet been established. This study aimed to investigate the effects ALA as an adjunctive therapy that protects against the occurrence of ALI and AKI in patients with major PPH.
| Patients and methods|| |
This randomized, double-blinded, placebo-controlled study was conducted in the obstetric ICU in Ain Shams University Hospitals. The protocol was approved by the Ethical Research Committee at Ain Shams University. Written informed consent was obtained from patients' first-degree relatives.
Forty patients of ASA physical status I-II (aged 18-40 years) admitted to Ain Shams Obstetric ICU from June 2013 to July 2014 were included in the study. Inclusion criteria were gestational age of at least 28 weeks and major PPH. Major PPH was defined as a blood loss greater than 2500 ml within 24 h after birth . The blood loss is measured by the subjective assessment of soaked swabs, estimation of blood clots, and blood in the suction bottle, along with the objective assessment of fall in hemoglobin and hematocrit levels after ICU admission and need for blood transfusion. Exclusion criteria were patients with renal impairment and severe chronic disease.
Active management of third stage of labor is offered to all women. All patients were followed up and vital signs were monitored. The following data were recorded:
All women were studied on postpartum day 0. They received standard therapy for major PPH based on Ain Shams Obstetric ICU protocol. Patients were randomly assigned to one of the two groups; randomization was attained by using computer-generated randomization list.
- Mode of delivery (spontaneous vaginal, instrumental vaginal, elective cesarean section, or emergency cesarean section).
- Possible cause of PPH (uterine atony, vaginal injuries and hematoma, adherent placenta, cervical tear, or uterine angle extension).
- Medical interventions (additional uterotonics including oxytocin, ergometrine, carboprost, and misoprostol).
- Conservative interventions (examination under anesthesia, intrauterine tamponade balloon, intrauterine packing, suturing of vaginal, cervical, or uterine angle tears, drainage of vaginal hematoma, securing the bleeder, manual removal of placenta and uterine compression sutures such as B-Lynch suture, pelvic arterial surgical ligation).
- Major interventions (laparotomy and cesarean hysterectomy).
Group 1, the ALA group (20 patients), received intravenous 1200 mg ALA in 500 ml of 0.9% isotone saline solution over 60 min once daily for 3 days.
Group 2, the placebo group (20 patients), received 500 ml of 0.9% isotone saline solution over 60 min once daily for 3 days.
For blinding, the IV container and line were covered with aluminum foil in both groups because the ALA-containing solution has yellow color and should be protected from light. All investigators and participants were blinded to the randomization of the study drug assignments.
The primary study outcome was the serum levels of markers of oxidative damage and inflammatory response. The secondary outcomes were the incidence of ALI and AKI. All samples were withdrawn before drug therapy at day 0 as baseline values and following the last dose - that is, at day 3. The following parameters were measured and recorded: thiobarbituric acid reactive species (TBARS) as an index of oxidative stress and interleukin-6 (IL-6) concentration, which is a general marker of proinflammatory response.
ALI was defined using the consensus definition of ALI : new onset hypoxemia or deterioration demonstrated by PaO 2 /FiO 2 less than 300 mmHg, with bilateral pulmonary changes, in the absence of cardiogenic pulmonary edema. Cardiac failure was diagnosed if two of the following were present: central venous pressure greater than 15 mmHg, a history of heart failure or valve dysfunction, ejection fraction less than 45% as estimated with echocardiogram, or a positive fluid balance.
In addition, serum creatinine (sCr) level was measured to identify and classify patients with kidney injury every 48 h. AKI was considered as 50% or 0.3 mg/dl increase in sCr level following surgery . Moreover, serum neutrophil gelatinase-associated lipocalin (sNGAL) was measured using the enzyme-linked immunosorbent assay method at day 0 and 1.
Group sample sizes of 20 per group will achieve 80% power to determine a relative difference in plasma oxidative damage parameters with a difference of −0.7 between the two groups, assuming the means are 0.3 in group 1 and 0.9 in group 2 with estimated group SDs of 0.6 and 1.0 and a significance level (a) of 0.05000 using a two-sided Mann-Whitney test assuming that the actual distribution is uniform.
Statistical analysis was carried out on a personal computer using the Statistical Package for Social Sciences, version 16.0 (SPSS© v. 17.0; SPSS Inc., Chicago, Illinois, USA). Qualitative data were analyzed with the c2 -test and were presented as n (%). Quantitative data were analyzed using unpaired Student's t-test for between-group comparison; data were presented as mean (SD). Nonparametric data were analyzed using the Mann-Whitney test and were presented as median (interquartile range). A P value less than 0.05 was considered statistically significant.
| Results|| |
Forty patients with major PPH admitted to the Ain Shams Obstetric ICU were included in the study. Patients were randomly assigned to one of the two equal groups: the ALA group and the placebo group. Both groups were comparable as regards demographic data as well as data of third stage of labor [Table 1].
The levels of oxidative damage markers (TBARS) were comparable for both groups at ICU admission (day 0). At day 3, TBARS levels in the ALA group were significantly decreased compared with that in the placebo group and baseline levels. Similarly, the levels of inflammatory response markers (IL-6) were comparable for both groups upon ICU admission (day 0). At day 3, IL-6 levels in the ALA group were significantly decreased compared with that in the placebo group and baseline levels, whereas in the placebo group there was a significant increase in the IL-6 levels compared with baseline [Table 2].
Baseline sNGAL at day 0 showed an increase in both groups, but the difference between the groups was not significant (P = 0.95). At day 1, sNGAL levels in the placebo group were significantly higher compared with that in the ALA group (P = 0.015) and baseline levels (<0.001) [Figure 1]. AKI developed in one (5%) patient in the ALA group versus five (25%) patients in the placebo group 48 h after ICU admission (P = 0.445). The level of sCr at ICU admission (day 0) and on day 1 was comparable between the groups. There was a significant difference as regards sCr levels on day 2 and day 3 between the two groups (P = 0.001 and 0.012, respectively) [Figure 2].
|Figure 1: Serum neutrophil gelatinase-associated lipocalin (SNGAL): the middle line in each box represents the median; the outer margins of the box represent the interquartile range; and the whiskers represent the|
minimum and maximum for each time point
Click here to view
|Figure 2: Serum creatinine: the middle line in each box represents the median, the outer margins of the box represent the interquartile range; and the whiskers represent the minimum and maximum for each time point|
Click here to view
Four patients (20%) in the ALA group and two patients (10%) in the placebo group required ventilator support at ICU admission (day 0). At day 3, the percentage of patients receiving ventilator support was reduced in the ALA group from 20 to 10% but it was not significant, whereas in the placebo group there was significant increase in the percentage of patients receiving ventilator support (from 10 to 35%). The oxygenation index (PaO 2 /FiO 2 ) reached less than 300 in 10% of patients in the ALA group and in 30% of patients in the placebo group, but there was no significant difference between the two groups [Table 3].
| Discussion|| |
This study aimed to investigate the effects of ALA as an adjunctive therapy that protects against the occurrence of ALI and AKI in patients with major PPH. This study demonstrated that ALA decreases markers of oxidative stress and inflammatory response and also has a preventive effect on the progression of ALI and AKI in patients with major PPH.
PPH is a major cause of maternal morbidity and mortality. According to the WHO, PPH accounts for approximately one-quarter of all maternal deaths worldwide and approximately half of all postpartum deaths in low-income countries .
Oxidative stress generated by I/R causes increased responsiveness of the immune system . Oxidative stress causes inflammatory cascade activation in acute hypovolemic hemorrhagic shock even in the absence of resuscitation procedures . This renders resuscitated hemorrhagic shock patients susceptible to the development of a systemic inflammatory response and organ dysfunction.
ALA and its reduced form, dihydrolipoic acid, is one of the most powerful biological antioxidant systems . They can quench broad range of ROS, chelate metals, interact with and regenerate other antioxidants, and they do not exhibit any serious side effects . Transfusion therapy is the mainstay of management of major PPH in addition to uterotonic agents and surgery . Clinical guidelines for the management of PPH are based on expert opinion and low level of evidence. Animal studies have identified that ALA can prevent AKI and ALI [23-25]. The lack of studies on human has hampered our ability to translate these promising therapies to patients with major PPH. The dose of 1200 mg/day ALA was chosen on the basis of a previous study that reported therapeutic doses in humans ranging from 200 to 1800 mg ALA/day [26-32].
Numerous assays provide indirect evidence of ROS activity, which includes measurement of consumption of endogenous antioxidant substances such as GSH, superoxide dismutase, and catalase. Other biochemical markers of the oxidative state are the end products of lipid peroxidation, including malondialdehyde and TBARS . In the current study, the use of ALA decreased the levels of oxidative damage markers (TBARS). The TBARS offer a view on the complex process of lipid peroxidation. The reduction of peroxidation by thiol compounds was observed by many authors [34-37].
IL-6 is an essential component of the postresuscitation inflammatory cascade in hemorrhagic shock . Moreover, it acts as a chemoattractant to alveolar macrophages and endothelial cells, causing an exacerbation of inflammatory response and ALI . In the current study, IL-6 was significantly decreased in the ALA group.
Acute respiratory distress syndrome (ARDS)/ALI after resuscitated hemorrhagic shock is an important contributor to late morbidity and mortality [40,41]. This injury is characterized by accumulated neutrophils in lung tissue, representing the main sources of ROS generation, adhesion molecule expression in the endothelium of pulmonary capillaries, and increased cytokine expression [42,43]. In addition to ROS production by polymorph nuclear cells, development of an inflammatory cascade originating from endothelial cells present in the pulmonary parenchyma has a secondary oxidative effect that aggravates the primary damage .
Levels of reactive species correlate with both the outcome of the disease and the severity of the injury to the alveolar epithelium . Antioxidant enzymes are useful in decreasing the severity of ARDS. Endogenous antioxidants, particularly GSH, normally constitute an effective control of toxic oxygen. Patients with ARDS have a marked decrease of GSH in epithelial lining fluid, plasma, and blood cells. GSH depletion in plasma and granulocytes is reversible by ALA-mediated GSH rescue .
At ICU admission, both groups were similar as regards the severity of illness and the need for ventilator support. Fewer patients in the ALA group were receiving mechanical ventilation support at day 3. Oxygenation index, which is a sensitive marker of the severity of acute respiratory failure and prognosis, reached less than 300 in fewer patients in the ALA group. The present study suggests that ALA has a preventive effect on the progression of ALI.
AKI is largely asymptomatic, and establishing the diagnosis currently depends on functional biomarkers such as sCr. sCr is a delayed and unreliable indicator of AKI [47,48]. Several studies have identified interventions that can prevent and/or treat AKI if instituted early in the disease course, well before the sCr begins to rise. NGAL is a useful early AKI marker that predicts the development of AKI in critically ill adult patients [49-53]. Serum NGAL increases a few hours after a nephrotoxic or ischemic condition . On analysis, it was observed that sNGAL levels were significantly lower in patients receiving ALA compared with placebo at day 1.
| Conclusion|| |
The current study demonstrates that ALA decreases plasma oxidative stress parameters and decreases plasma IL-6 levels. These alterations are related to the development of ALI and AKI after hemorrhagic shock. Accordingly, ALA could be considered as an adjunctive therapy in ALI and AKI after major PPH.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]