 Abstract | | |
Hemoglobin (Hb)-based transfusion triggers are the most commonly used transfusion triggers in clinical practice at present, despite of having many drawbacks. In daily clinical practice, the traditional 10/30 rule (Hb 10 g/dL – hematocrit 30%) has been the most commonly used trigger for blood transfusions. The physiological rationale for this approach is that both Hb and hematocrit are key determinants of arterial oxygen delivery (DO2) and thus the lower limit of oxygen transport and adequate tissue oxygenation. Transfusions with allogeneic red blood cells (RBCs) can be avoided in most patients with Hb thresholds above 7 g/dL with stable hemodynamics. Although physiological transfusion triggers appear to be the most suitable for blood transfusion yet due to the lack of sufficient clinical trials their significance has not been proved. Venous oxygen saturation (SvO2), central venous oxygen saturation, arterial lactate, and near-infrared spectroscopy, when combined together seem to be most useful in avoiding premature blood transfusion. However, large clinical trials are needed to prove their suitability. Blood centers faced a huge challenge in devising a preparedness strategy to withstand COVID-19 outbreak globally. A drastic fall in the red cell inventory was observed as compared to pre-COVID-19 time period due to disproportionate decrease in blood collection and demand. A restrictive transfusion strategy was also applied in hospitals using a threshold for transfusion based on a drop in the Hb level below 7 g/dl in patients with stable hemodynamics. In patients having anemia with acute coronary syndromes, the RBCs transfusion threshold is when Hb levels fall below 8 g/dl and hematocrit below 24%. There was an increase in the demand of convalescent plasma in the initial phase of the pandemic as its benefits were overestimated. The efficacy and safety of convalescent plasma are questionable. Implementation of the most recent evidence-supported transfusion guidelines and eliminating unnecessary transfusions are considered the main goals of patient blood management programs during COVID-19 pandemic.
Keywords: COVID-19, goal-directed therapy, transfusion triggers
How to cite this URL:
Chauhan R, Singh M. Do we have different transfusion practices in COVID-19 and non-COVID-19 patients?. Asian J Transfus Sci [Epub ahead of print] [cited 2023 Jan 28]. Available from: https://www.ajts.org/preprintarticle.asp?id=363241 |
| Introduction | |  |
For years, one way to guide the physician's decision for or against transfusion was the use of the hemoglobin (Hb) concentration or the hematocrit.[1] Transfusion trigger is defined as the value of Hb below which red blood cell (RBC) transfusion is indicated. The transfusion target is the Hb one aims to achieve after RBC transfusion.[2] In daily clinical practice, the traditional 10/30 rule (Hb 10 g/dL – hematocrit 30%) has been the most commonly used trigger for blood transfusions.[3] The physiological rationale for this approach is that both Hb and hematocrit are key Arterial oxygen delivery (DO2) and thus the lower limit of oxygen transport and adequate tissue oxygenation. However, this approach neglects the fact that oxygen transport capacity and tissue oxygenation are critically influenced by compensatory mechanisms of the cardiovascular system and the microcirculation.[1] Transfusion of blood and blood products requires appropriate calculations and measures. Thus, the aim of this article was to define the blood transfusion triggers and its related physiology so that COVID-19 or non-COVID-19 patients receive appropriate transfusions.
Different measures aim at improving patient outcomes by combining three “patient blood management (PBM) pillars.” The three PBM pillars are: (1) Hb concentration, (2) hemostasis, and (3) blood loss.[4] Of these three, one is to utilize anemia tolerance of a specific patient in a rational way.[4] Anemia tolerance has been investigated in the past, especially in situations where the transfusion of RBCs was impossible or declined. The most famous examples for the latter situation are Jehovah's Witnesses who decline the transfusion of RBCs for religious beliefs. It has been shown in these patients that anemia tolerance is much lower than generally anticipated, and therefore, transfusion above Hb values of 8 g/dL might be needless.[5] Hébert et al. were the first to demonstrate this in a general intensive-care unit population and initiated a large amount of studies that investigate a liberal versus a more restrictive transfusion regime.[6] Since then, a plethora of studies has demonstrated that avoiding premature transfusion results in a substantial reduction of overall RBC usage without compromising organ function or survival.[7]
It is still a challenge to differentiate between “premature” and “adequate” transfusion and determine the individual limits of anemia tolerance. Many studies highlight that moderate and even mild anemia is a significant perioperative risk factor implicating that it might be advisable to avoid any degree of anemia in surgical patients as far as possible.[8],[9] However, it cannot be concluded from the data that the restoration of normal Hb levels by transfusing RBCs reverses any anemia-related increase in mortality.
Huge amount of literature has been published on the effects of a liberal versus restrictive transfusion regimen (i.e., higher or lower Hb as transfusion threshold) on outcome.[10] Transfusing at a restrictive Hb concentration of between 7 and 8 g/dL decreased the proportion of participants exposed to RBC transfusion by 43% across a broad range of clinical specialties. There was no evidence that a restrictive transfusion strategy impacts 30-day mortality or morbidity (i.e., mortality at other points, cardiac events, myocardial infarction, stroke, pneumonia, thromboembolism, and infection) compared with a liberal transfusion strategy. The findings provide good evidence that transfusions with allogeneic RBCs can be avoided in most patients with Hb thresholds above 7–8 g/dL.[9] The results of these trials formed the majority of the current scientific evidence and informed most guidelines on RBC transfusion.[11] As a consequence, most of these guidelines primarily focus on an Hb-based transfusion trigger and only some of them essentially integrate the concept of physiological transfusion triggers to find the optimal time point for transfusion.[12] During COVID-19 pandemic the concepts of blood and its components transfusion were revisited and it was redefined at all fronts. It was need based, symptomatology based, and transfusion triggers took different shapes.
The present article discusses various blood transfusion triggers, their rationale and their role in early goal-directed therapy (EGDT) in pre-COVID-19 pandemic era and COVID-19 times.
| Transfusion Triggers | | |
The trigger for transfusion has become more conservative or restrictive over the years.[2] The decision to transfuse blood is based not only on the laboratory values but also on the objective evaluation of the patient's clinical condition and the ability to compensate for the blood loss. Various factors taken into account before transfusion are the patient's age, comorbidities, severity of illness, and the rate and amount of hemorrhage. From univariable analysis, the factors significantly associated with red cell transfusion in first-time elective. Coronary artery bypass graft patients were patients' age, gender, body weight, preoperative Hb level, cardiopulmonary bypass (CPB) time, chronic renal failure, and smoking status.[13] The probability of transfusion was higher with increasing age and CPB time while body weight and preoperative Hb level were inversely related.
Oxygen demand can range from 2.9 ± 0.4 mL/kg/min for resting elderly women to > 50 mL/kg/min in sporting, young men, and close to 100 mL/min/kg among professional athletes at maximum performance.[14] Accordingly, the respiratory and cardiovascular systems need physiological mechanisms to adjust DO2 to a broad range of oxygen demands. DO2 is mainly determined by three factors: cardiac output (CO), Hb, and Hb oxygenation.
DO2 = (Hb × 1.34 × SaO2 + 0.0031 × PaO2) × CO
where SaO2 is arterial oxygen saturation and PaO2 arterial partial pressure of oxygen. Even under resting conditions, DO2 exceeds oxygen demand by about 4-fold.[15]
Animal models suggest that this critical DO2 limit is approximately 9–11 mL/kg/min for anemia, hypoxia, or low CO.[16] But even at higher Hb values, and by that higher DO2 thresholds, acute anemia seems to influence survival. Tobian et al. demonstrated that the survival time of Jehovah's Witnesses dying with acute anemia essentially depends on the Hb value, giving the physician a window of opportunity to intervene depending on the actual Hb value.[17] These results clearly demonstrate that not only a DO2 close to or below 10 mL/kg/min should be avoided, but that even higher thresholds might be dangerous, probably due to additional mechanisms. In 293 patients, the odds of death increased 2.04 times for each 1.0 g/dL decrease in nadir Hb.[18] Overall mortality rate was 8.2% (95% confidence interval, 5%–11.3%). This study confirmed the previously reported low risk of mortality in upper nadir Hb ranges of 7–8 g/dL and much higher risk in lower ranges. Although the critical DO2 is used as a general concept for determining anemia tolerance, it is unlikely that a clear limit can be drawn from these values.[18]
Many clinical trials in the last few decades have found restrictive transfusion strategy to be as safe as conventional strategy. A Cochrane meta-analysis published in 2012 which included 6264 patients in 19 such trials in the settings of surgery (including cardiac surgery), critical care, trauma, and acute hemorrhage found that the use of restrictive transfusion strategy (Hb: 7–9 g/dl) led to 39% fewer patients receiving transfusion (risk ratio [RR]: 0.61 [0.52–0.72]) and a decrease in the total number of transfusions (mean decrease 1.19 [1.85–0.53]) compared to liberal strategy (Hb: 9–12 g/dl).[10] Two randomized-controlled trials (RCTs) had adequate power to assess mortality and were major contributors to this meta-analysis.[19]
Case reports highlight survival with Hb as low as 20 gl − 1 and experimental studies have shown that young healthy adults can compensate for Hb as low as 40 gl − 1 without significant deleterious effects if the circulating blood volume is maintained with fluids.[20] However, acutely unwell and elderly patients, especially those with comorbidities, are less likely to tolerate such low levels. Hb concentration, in the absence of other specific clinical and laboratory tests, remains the most widely used trigger for blood transfusion in clinical practice.[21]
There exists a hierarchy of transfusion triggers in daily clinical practice. Hb/hematocrit remains on the top. Physiological transfusion triggers include systemic oxygen delivery (DO2), electrocardiogram (ECG), near-infrared spectroscopy (NIRS), central venous oxygen saturation (ScvO2), and mixed venous oxygen saturation (SvO2).[3] They have low sensitivity and specificity to predict the need for RBC transfusion.
Current transfusion guidelines recommend that RBCs should not be transfused at an Hb ≥10 g/dL (with the potential exception of univentricular pediatric cardiac surgery), while RBC transfusion is nearly always recommended at an Hb <6 g/dl.[11] Most guidelines recommend applying an Hb threshold of 7 g/dL in relatively “healthy” patients, whereas patients with cardiovascular compromise should be transfused at an Hb of 8 g/dl.[1] These thresholds are based on the results of many clinical trials comparing the outcome effects of a restrictive transfusion regimen (transfusion threshold near 7–8 g/dl) to a liberal one (transfusion threshold of 9 g/dl).[21],[22],[23],[24]
| Physiological Transfusion Triggers | | |
Physiologic transfusion triggers should progressively replace arbitrary Hb-based transfusion triggers.[25] These “physiologic” transfusion triggers can be based on signs and symptoms of impaired global oxygenation (lactate, venous O2 saturation [SvO2]) or, even better, of regional tissue oxygenation (electrocardiographic ST-segment and electroencephalographic P300 latency). There are many factors which limit their use in clinical practice.[11]
| Oxygen Delivery to the Tissues | | |
Oxygen delivery to the tissues (DO2) begins to decrease at hematocrit values lower than 25% (corresponding to a Hb concentration of ~8 g/dL).[26] At hematocrit values of ~25%, the compensation of dilutional anemia through an increase in CO becomes exhausted and DO2 starts to decrease. However, since DO2 exceeds oxygen demand under physiological conditions by a factor of three to four, the organism's oxygen demand (reflected by total body oxygen consumption-VO2-under quiescent conditions) can be met over a large range despite a decreasing DO2 (oxygen supply independency of VO2) [Figure 1]. | Figure 1: Relationship between oxygen consumption (VO2) and oxygen delivery (DO2)
Click here to view |
Over a long period, VO2 remains independent of DO2 despite the anemia-related decrease of DO2 (oxygen supply-independency of DO2). When a critical Hb concentration (is reached, DO2 falls short of the actual oxygen demand and VO2 begins to decrease (onset of oxygen supply-dependency of VO2).
Inter dependency is seen between Hb, SaO2, PaO2, and CO. An increase in any of these parameters results in decrease in the other. Due to these interdependencies, the use of DO2 as a transfusion trigger is not practically possible as the effect of any potential intervention is difficult to judge.
| Mixed Venous Oxygen Saturation (SvO2) and Central Venous Oxygen Saturation | | |
Increase in oxygen demand regularly decreases SvO2 and the main compensatory mechanism in this situation is an increase in oxygen extraction in the microcirculation. If DO2 is decreased by normovolemic anemia, there is usually a certain time point when SvO2 decreases.[27] This time point is often referred to as a potential transfusion threshold as it could indicate that other compensatory mechanisms fail to maintain sufficient oxygen delivery.[28] In a study by Surve et al., ScvO2 <70% and Hb threshold of 7 g/dl appeared to be a useful physiological trigger for deciding the need for blood transfusion in brain-injured patients.[29] In another study by Retter et al., during the early resuscitative phase of severe sepsis, if there is evidence of inadequate oxygen delivery to the tissues (ScvO2 4 mmol/L), blood transfusion is considered to achieve a target Hb of 9–10 g/dl.[30] However, in a multicentric RCT Transfusion Requirements in Septic Shock trial in 1000 patients with septic shock in 32 intensive care units (ICUs), there was no difference in the 90-day mortality (RR 0.94 [0.78–1.09]), the number of patients with ischemic events (0.90 [0.58–1.39]) or in the use of life support in patients receiving leukoreduced RBCs at a transfusion trigger of 7 or 9 g/dl.[31]
In conditions like septic shock, SvO2 frequently remains high despite tissue hypoxia.[25] Under these conditions, RBC transfusion may even decrease DO2 and could be considered potentially harmful. All these considerations also apply for ScvO2 as a potential transfusion trigger, but ScvO2 has the additional drawback of reflecting the oxygen balance of the upper part of the body rather than the lower part, which further reduces its usefulness.[3]
| Electrocardiogram | | |
ECG has been used to detect myocardial hypoxia in acute anemia and appears to be an interesting technique to determine the individual transfusion trigger, particularly in patients with cardiovascular risk factors.[32] In a study by Pappachan et al.[33] demonstrated that changes in the ST segment correlate well with the extent of acute anemia. There was a statistically significant positive correlation between change in ST segment and Hb with a regression coefficient of −0.132. But so far, no large clinical trial has so far investigated the safety of using ECG changes as a transfusion trigger.
| Arterial Lactate | | |
Lactate could potentially be used as a physiologic RBC transfusion trigger, although there are some limitations to its interpretation.[34] If Hb declines to such a degree that tissue oxygen demand can no longer be met, tissue hypoxia occurs resulting in a rise in lactate levels. The lactate concentration can then be determined easily and cost-effectively. Transfusion guidance by measuring lactate levels plays a clinical role only in patients with trauma-associated bleeding or sepsis with concomitant anemia.[35] In a study by Weiskopf et al.[36] it was found that lactate levels did not increase until Hb levels dropped below 5 g/dL. As lactate levels only increase when tissue oxygen supply is not met for a longer period, increases in lactate levels are not observed in the case of short-term tissue hypoxia. Furthermore, there are several other reasons for the rise in arterial lactate levels besides increase in oxygen demand by the tissues.[37] There have been no trials or studies clearly indicating the significance of using lactate levels as effective transfusion trigger.
| Near-Infrared Spectroscopy | | |
It is not only a routine tool but it also has a tremendous research potential which can provide unique information not provided by any other technique.[38] It is a method that allows noninvasive measurement of the summative oxygen saturation of a tissue. The reason it is being recommended as a transfusion trigger is that a severe decrease in regional oxygen saturation is associated with a deterioration in tissue oxygen supply. If a decrease in regional oxygen saturation occurs, it is often assumed that an intervention, typically the transfusion of RBCs in the context of anemia, restores tissue oxygen.[39] A study by Serraino et al. has shown that RBC transfusions can increase NIRS values.[40] Whether this increase in regional oxygen saturation actually reflects an improvement in tissue oxygenation, or rather a decrease in oxygen depletion is still not clear.
| Goal-Directed Therapy and Transfusion: Does it Impact Transfusion Trigger? | | |
Goal-directed therapy has been used for severe sepsis and septic shock in the ICU. This approach involves adjustments of cardiac preload, afterload, and contractility to balance oxygen delivery with oxygen demand.[41] EGDT has generated a lot of interest in treatment of the patients with severe sepsis and septic shock. EGDT is a protocolized resuscitation strategy to specified end-points in the management of sepsis. In particular, titrating crystalloid, blood products, and vasoactive agents to static physiological indices, such as central venous pressure of 8–12 mmHg, urine output >0.5 mL/kg/h, mean arterial pressure >65 mmHg, and mixed venous oxygen saturation (SmvO2) over 65% among other end points, including early administration of antibiotics.[42]
A study by Rivers et al. showed significantly improved survival with EGDT in comparison to the then standard therapy.[41] Of the 263 enrolled patients, 130 were randomly assigned to early goal-directed therapy and 133 to standard therapy; there were no significant differences between the groups with respect to base-line characteristics. In-hospital mortality was 30.5% in the group assigned to early goal-directed therapy, as compared with 46.5% in the group assigned to standard therapy (P = 0.009).
Transfusion of RBCs is a central part of many protocols of early goal-directed therapy to indicate the need for use of inotropes and RBCs, as both central venous saturation and hematocrit are used as transfusion triggers.[43]
In previous EGDT protocols, transfusion of RBC targeting Hb >8 g/dL or hematocrit level > 30% is a key element to increase ScvO2.[41] However, evidence for augmentation of oxygen delivery and increase of ScvO2 more than 70% by RBC transfusion is poor. On the contrary, a rational use of RBC transfusion is mandatory, as they are associated with increased morbidity and mortality.
In the process trial, 1341 patients with septic shock were randomly assigned to one of three groups for 6 h of resuscitation.[44] The three groups were protocol-based EGDT including RBC transfusion if hematocrit <30% and central venous saturation <70%; protocol-based standard therapy or usual care. EGDT group patients received more vasopressors (54.9% vs. 44.1%, P = 0.003), more dobutamine (8.0% vs. 0.9%; P < 0.001), and more RBC transfusion (14.4% vs. 7.5%; P = 0.001) in comparison to the other two groups without any clinical benefit but used more resources. Similar results were obtained in ARISE trial where 1600 patients with early septic shock were randomly assigned to receive either EGDT or usual care.[45] The primary end point was all-cause mortality within 90 days. The two studies demanded a reassessment of transfusion trigger hematocrit <30%.
Holst et al. compared two different transfusion strategies and randomized 1005 patients with septic shock to receive one unit RBC when the Hb level was ≤7 g/dl (lower threshold) or when the level was ≤9 g/dl (higher threshold) during the ICU stay.[24] The primary endpoint was mortality at 90 days that was similar between both groups. However, the lower-threshold group received a median of 1 unit of blood (interquartile range, 0–3) and the higher-threshold group received a median of 4 units (interquartile range, 2–7). These authors concluded that RBC transfusion at an Hb threshold of 7 g/dl is safe in septic patients, and a higher threshold was not beneficial and resulted in a 10–20 times higher transfusion adverse events.
The World Health Organization has adopted resolution 63.12, also adopted by the United States Department of Health and Human Services, recommending all member states to implement a PBM program.[43] PBM is a proactive, evidence-based approach to identify, diagnose and treat anemia before a transfusion threshold is met.
Many EGDT protocols contain transfusion of RBC targeting Hb >8 g/dL or hematocrit level >30% as a key element to increase ScvO2.[43] Though RBC transfusions are associated with increased morbidity and mortality, PBM program should be incorporated within the EGDT protocols so as to minimize the unnecessary exposure to blood products.
Blood centers faced a huge challenge in devising a preparedness strategy to withstand COVID-19 outbreak globally. SARS-CoV-2 pandemic outbreak had major ripple effects on the maintenance of blood inventory. A drastic fall in the red cell inventory was observed as compared to pre-COVID-19 time period due to a disproportionate decrease in blood collection (1/6–1/9 of the previous collection) and demand (1/2 of the previous demand).[46] Formulating and implementing local mitigation strategies and following them strictly can go a long way in maintaining blood inventory during a pandemic.[47] A buffer stock of blood and blood components, strict adherence to the transfusion triggers, good coordination with the clinical staff, and a prospective review of blood transfusion requests to ensure rational blood transfusion were some of the steps which helped to successfully maintain transfusion requirements in the initial phases of the COVID-19 pandemic.[46]
Reports have shown that blood donations dropped precipitously during the COVID-19 outbreak.[48] Currently, during the COVID-19 outbreak, daily communication between the blood bank, key clinical teams, and blood centers has played a vital role in ensuring and predicting the sustainable inventory of blood products to meet patient needs, especially for massive transfusion protocol.[49] A restrictive transfusion strategy was also applied in the hospital using a threshold for transfusion based on a drop in the Hb level below 7 g/dl in patients with stable hemodynamics.[50] In patients having anemia with acute coronary syndromes, the RBC transfusion threshold is when Hb levels fall below 8 g/dl and hematocrit below 24%. In nonbleeding patients, restricting blood transfusions by using a Hb trigger of <7 g/dL significantly reduces cardiac events, re-bleeding, bacterial infections, and total mortality.[22] In a study by Beverina et al., the mean Hb at transfusion was 7.7 g/dL and a slightly liberal approach was applied during the transfusion of ICU patients with COVID-19 disease.[51] It may be needed to consider increasing the threshold level of Hb at which the patient needs to be packed RBCs, especially in COVID-19 patients with hypoxic features.[52]
Plasma is given in patients who need urgent warfarin reversal having international normalized ratio >1.7, clinical coagulopathy based on relevant laboratory and thromboelastography values, factor V, and XI deficiency. Plasma is being misused quite frequently, and there is overestimation of its benefits in nonbleeding patients. In compliance with these transfusion strategies, blood components were successfully provided in massive transfusion protocol during the outbreak.[49]
Implementation of the most recent evidence-supported transfusion guidelines and eliminating unnecessary transfusions are considered the main goals of PBM programs during major disasters.[53] Hospitals and academic medical centers across the nation are beginning to develop bloodless medicine and PBM programs in response to the favorable evidence. Some of the strategies include evaluation of appropriateness of transfusion orders and further discussion with clinical team if needed, blood-sparing strategies during surgery, such as implementation of normovolemic or hemodilution measures or usage of cell salvage along with staff education and open communication is imperative. The blood type of trauma patients should be determined as rapidly as possible so that transfusion can be performed using type-specific RBC, thereby conserving the supply of group “O” RBC. Group “O negative” RBC should be reserved for women of childbearing age (<50 years) and female children. If platelet availability is limited, the units can be split into two doses as one-half unit of platelets is enough to clinically benefit most of the patients. It basically depends on the clinical condition of the patients.[53]
Moreover, despite current guidelines, as shown by a recent worldwide audit, the transfusion thresholds applied in “real-life” seems slightly higher than recommended (Hb 8.3 ± 1.7 g/dL).[54]
There was an increase in the demand of convalescent plasma in the initial phase of the pandemic as its benefits were overestimated. To cope up with the increased demand, blood banks had to frame strategies like communicating with the concerned clinicians regarding the clinical severity of the COVID-19-positive patients and their laboratory parameters. History about the use of convalescent plasma antedates the recognition that randomized trials are needed for ultimate proof of efficacy and safety due to the highly variable course of COVID-19 illness.[55] Thousands of units of plasma, almost all untested for antiviral neutralizing titers, have been transfused in the United States using Food and Drug Administration-approved emergency investigational new drug and expanded access protocols.[56] Many small randomized trials are being done, but in most cases, no specific titer of antibody in the plasma is specified. Hence, the efficacy and safety of convalescent plasma are questionable.
| Conclusion | | |
Hb-based transfusion triggers are the most commonly used transfusion triggers in clinical practice at present, despite having many drawbacks. Transfusions with allogeneic RBCs can be avoided in most patients with Hb thresholds above 7–8 g/dL. SvO2, ScvO2, arterial lactate, and NIRS when combined together seem to be most useful in avoiding premature blood transfusion. Although physiological transfusion triggers appear to be the most suitable for blood transfusion yet due to the lack of sufficient clinical trials their significance has not been proved.
Blood centers faced a huge challenge in devising a preparedness strategy to withstand COVID-19 outbreak globally. A drastic fall in the red cell inventory was observed as compared to pre-COVID-19 time period due to a disproportionate decrease in blood collection and demand. A restrictive transfusion strategy is applied in hospital using a threshold for transfusion based on a drop in the Hb level below 7 g/dl in patients with stable hemodynamics. In patients having anemia with acute coronary syndromes, the RBC transfusion threshold is when Hb levels fall below 8 g/dl and hematocrit below 24%. There was an increase in the demand of convalescent plasma in the initial phase, but later on, many trials were done, and its efficacy and safety are still questionable. However, in recent COVID-19 pandemic, implementation of the most recent evidence-supported transfusion guidelines and eliminating unnecessary transfusions are considered the main goals of PBM programs.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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| 56. | |
Correspondence Address:
Rupali Chauhan,
House Number-66, Satyanarayan Nagar, Behind Balaji Temple, Anjar, Kutch, Gandhidham - 370 110, Gujarat
India
 Source of Support: None, Conflict of Interest: None DOI: 10.4103/ajts.ajts_82_22
[Figure 1] |
