European Journal of Cardiovascular Medicine

Septic shock is a potentially fatal medical condition that occurs when sepsis, which is organ injury or damage in response to infection, leads to dangerously low blood pressure and abnormalities in cellular metabolism. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) defines septic shock as a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone. Patients with septic shock can be clinically identified by requiring a vasopressor to maintain a mean arterial pressure of 65 mm Hg or greater and having serum lactate level greater than 2 mmol/L (>18 mg/dL) in the absence of hypovolemia. This combination is associated with hospital mortality rates greater than 40%.[1] Albumin is the main protein responsible for plasma colloid osmotic pressure[2]; it acts as a carrier for several endogenous and exogenous compounds,[3] with antioxidant and antiinflammatory properties, and as a scavenger of reactive oxygen[4,5 ]and nitrogen[6 ]species and operates as a buffer molecule for acid–base equilibrium.

The key role in the development of severe sepsis is played by an immune and coagulation response to an infection. Both pro-inflammatory and anti-inflammatory responses play a role in septic shock.^[7] Septic shock involves a widespread inflammatory response that produces a hypermetabolic effect. This is manifested by increased cellular respiration, protein catabolism, and metabolic acidosis with a compensatory respiratory alkalosis.^[8]

Most cases of septic shock are caused by gram-positive bacteria,^[9] followed by endotoxin-producing gram-negative bacteria, although fungal infections are an increasingly prevalent cause of septic shock.^[8] Toxins produced by pathogens cause an immune response; in gram-negative bacteria these are endotoxins, which are bacterial membrane lipopolysaccharides

There is a convincing rationale for the potential advantages of albumin administration during severe sepsis. Albumin is the main protein responsible for plasma colloid osmotic pressure; it acts as a carrier for several endogenous and exogenous compounds, with antioxidant and antiinflammatory properties, and as a scavenger of reactive oxygen and nitrogenspecies and operates as a buffer molecule for acid–base equilibrium.

Septic shock syndrome resulting from systemic inflammation and excessive host immune responses to infection is a top cause of death in hospitalized patients, with 40–50%mortality[.8,9]]Acute kidney injury (AKI) is a common complication of septic shock.[10] It accounts for approximately 80% of all septic shock patients[.11] Early reasonable fluid resuscitation followed by vasopressor is one of the most important strategies for initial treatment in patients with septic shock

Human serum albumin (HSA) has been considered for the treatment of septic shock in initial fluid resuscitation because of its advantages of restoring effective volume and maintaining colloidal osmotic pressure. Whether albumin can improve patient-centered outcomes beyond expanding blood volume, however, is uncertain. Based on weak recommendation, the latest Surviving Sepsis Campaign guidelines suggested albumin for the initial resuscitation when patients require substantial amounts of crystalloids. At present, the use of albumin for fluid resuscitation in the treatment of septic shock remains controversial. A multicenter randomized controlled trial (RCT) showed that albumin replacement in addition to crystalloids, as compared with crystalloids alone, did not improve the rate of survival at 28 and 90 days. But a subsequent meta-analysis of RCTs found that albumin infusion was associated with reduced 90-day mortality. Nevertheless, there is little available evidence from RCTs or guidelines to support its practice  among patients with septic shock. Therefore, further studies are needed to investigate the efficacy of albumin infusion in patients with septic shock Thus, this retrospective study mainly discussed the relationship between  early albumin infusion and outcomes in patients with septic shock.

Rationale :

Albumin is one of the major abundant proteins found in blood, which has major functions like maintaining osmotic pressure, transport of molecules, adequate nutrition, scavenging of toxins etc. There is a convincing rationale for the potential advantages of albumin administration during severe sepsis. Albumin is the main protein responsible for plasma colloid osmotic pressure. It acts as a carrier for several endogenous and exogenous compounds, with antioxidant and anti-inflammatory properties, and as a scavenger of reactive oxygen  and nitrogen species and operates as a buffer molecule for acid–base equilibrium. In sepsis ,due to hyperfusion of tissues there is a release of inflammatory mediators and oxygen radicals. If remain untreated these mediators again causes hypoperfusion and organ dysfunction. A vicious cycle is set causing worsening of organ dysfunction and organ failure. With the early administration of inj. albumin, the hypotension is treated before the vicious cycle sets in thereby preventing organ dysfunction[12,13]

Although crystalloids are more widely used for fluid resuscitation than colloids of all types, the proportion of resuscitation episodes specifically using human-derived colloid solutions (i.e. albumin) has increased. [14]Albumin has been found to have a favourable safety profile and, when compared with crystalloids, is slightly more efficacious as a plasma volume-expander and less likely to reduce renal blood flow from hyperchloremia (which can occur with the use of chloride-liberal solutions like isotonic saline).[15,16] However, some studies have indicated that albumin increases costs and its impact on mortality is unclear. It is the timing of albumin treatment in sepsis/septic shock which  may be an important determinant of its utility, as early treatment with albumin has been associated with a significantly increase chance of survival.[17]

In the International Guidelines for Management of Sepsis and Septic Shock 2021, albumin was suggested to be used for patients with septic shock who receive large volumes of crystalloids, notwithstanding a “weak” recommendation strength and merely moderate quality evidence.

 The Albumin Italian Outcome Sepsis (ALBIOS) trial revealed a tendency towards improved survival rates in patients with sepsis who received album for the correction of hypoalbuminemia. Subgroup analysis further demonstrated reduced mortality rates among patients with septic shock

AIM: Study the effect of  early supplementation  of injection albumin within first 24hours of developing septic shock with  first  lab report depicting serum albumin level <3gm/dl of  in  outcome of patients with septic shock

OBJECTIVES:

To know serum  albumin level  in the patients in septic shock of mean arterial pressure of less than 65 mmHg .

To study the effect of  early supplementation of  injection albumin on blood pressure of patients with septic shock.The early intervention is defined as the administration of inj albumin 20% 100 in initial phase  of septic shock with serum albumin below 3mg/dl

Data for retrospective longitudinal cohort  study of patients in SICU with septic shock  from period of 1 November 2022 to  31 oct 2024 in AIIMS Hospital, Nagpur will be retrieved from medical record department.

Data of serum albumin levels of patients admitted in SICU having  septic shock as recorded in the case sheet will be retrieved 

The data of patients having serum albumin  level below 3 gm/dl is taken as limiting standard .The data of patients who had albumin  level below 3gm/dl  and  were treated with 20%  injection albumin  100 ml once a day for  consecutive 3 days as per the standard regime will retrieved.

The patients treated  with  injection albumin within first 24hours of developing septic shock with  first  lab report depicting serum albumin level <3gm/dl of will be considered  as the early administration and will be included in the study group.

Stratification of Patient Data: Patients has been categorized based on key variables and any documented comorbid conditions, particularly those known to influence blood pressure such as pain, antihypertensive drugs ,immediate postoperative period, epidural analgesics etc . This stratification allowed  a more refined longitudinal study.

Detailed Data Collection on Relevant Variables: A comprehensive demographic and clinical data  gathered, including age, gender, weight, comorbidities, and specific surgical details. This  facilitated a module to study precisely thereby controlling for these variables statistically.

All possible confounding factors were  eliminated by virtue of  exclusion criteria e.g  Patients diagnosed with  all other possible  causes affecting decrease in blood pressure .Inclusion criteria was i)Patients  diagnosed with  septic shock (mean arterial pressure <65mmHg) in SICU during period of 1 November 2022 to 31 October  2024 ii)Patient receiving injection 20% albumin within 24 hours of developing  septic shock with lab report of serum albumin <3gm/dl iii) Age 20 to 50 years of age  iv) All gender.

Exclusion criteria: i)Patients  diagnosed with other causes of  shock ( cardiogenic shock, haemorrhagic shock, spinal shock etc)ii)patients on antihypertensive medications iii)Decompensated heart failure.iv)immediate postoperative period(within 24 hours of surgery)v)Pt treated with ongoing epidural analgesia.

Patients were also excluded from the study if they received albumin infusion 48 h after ICU admission. For a patient with more than one ICU admissions, only the first admission was included. According to the albumin infusion status within 48 h after ICU admission, the participants were separated into two groups: albumin group (intervention) and non-albumin group (control).

Demographic and laboratory variables

Statistics analysis

Continuous variables are expressed as median [interquartile range (IQR)] due to their non-normal distribution. The differences between groups were determined by the Mann–Whitney U test. Categorical variables are shown as frequencies and percentages. The comparisons were performed by the χ2 test or Fisher's exact test as appropriate.

To balance the baseline differences, propensity-score matching (PSM) was conducted with a caliper width of 0.2 logits of the standard difference. Patients were divided using 1:1 nearest neighbor matching, so that each person in the albumin group was matched with those in the non-albumin group. The standardized mean difference (SMD) was used to assess the effectiveness of PSM27 (Fig. 2).

The Cox regression model was performed to assess the relationship between albumin infusion and mortality after adjustment for confounding variables with P < 0.05 in univariate analysis (Supplementary Table S2. The logistic regression model was used to assess the impact of albumin infusion on the recovery. Various subgroups were classified by different age, lactate, AKI stage, congestive heart failure, chronic kidney disease (CKD) and liver cirrhosis. The association between the daily dose of albumin and 28-day mortality was also assessed (Supplementary Table S4). Table S5 showed that the correlation between other colloid solutions and 28-day mortality. Multivariate analysis by Cox regression was used in subgroup analyses after adjusting for potential confounders, which were performed after PSM.

Statistical analysis was carried out using software Stata 15.1 (https://www.stata.com/) and R 4.0.0 (https://www.r-project.org/) in the Windows operative system. Statistical significance was determined when the p value is less than 0.05.

Ethics approval and consent to participate

The study was an analysis of a third-party anonymized publicly available database with pre-existing institutional review board (IRB) approval. The Institutional review boards at the Beth Israel Deaconess Medical Center (protocol 2001-P-001699/14) and Massachusetts Institute of Technology (protocol 0403000206) have approved the data collection and the use of MIMIC-III for research purposes and granted waiver of informed consent. All methods were carried out in accordance with relevant guidelines and regulations.

Data availability

All data and material were available at https://mimic.mit.edu/.

Study design: Retrospective Longitudinal Cohort Study

SAMPLE SIZE AND SAMPLING TECHNIQUE : Software:www. openepi.com

Method Of Measurement Of Outcome Interest: laboratory investigations

Data Collection Methods: Data will be collected from the medical record of the patient’s IPD file.

Statistical Analytical METHODS: Statistical analysis was carried out using software Stata 15.1 (https://www.stata.com/) and R 4.0.0 (https://www.r-project.org/) in the Windows operative system. Statistical significance was determined when the p value is less than 0.05.

Patient ‘s  data be studied for the  patients admitted in SICU  during duration of 24 months  from SICU patients admitted from 1st Nov 2022 to 31/0ct 2024 .

Demographic data:

Changes in mean arterial pressure with timeline:

Table 2 shows the mean and standard deviation mean arterial blood pressure and the variations of mean arterial blood pressure after the stipulated elapse of time interval .

There is a convincing rationale for the potential advantages of albumin administration during severe sepsis.[1] Albumin is the main protein responsible for plasma colloid osmotic pressure [2]; it acts as a carrier for several endogenous and exogenous compounds, [3] with antioxidant and antiinflammatory properties, and as a scavenger of reactive oxygen [4,5] and nitrogen6 species and operates as a buffer molecule for acid–base equilibrium [.7]

Septic shock syndrome resulting from systemic inflammation and excessive host immune responses to infection is a top cause of death in hospitalized patients, with 40–50%mortality [.8,9]]Acute kidney injury (AKI) is a common complication of septic shock.[10] It accounts for approximately 80% of all septic shock patients[.11] Early reasonable fluid resuscitation followed by vasopressor is one of the most important strategies for initial treatment in patients with septic shock.

In sepsis, due to hyperfusion of tissues there is a release of inflammatory mediators and oxygen radicals. If remain untreated these mediators again causes hypoperfusion and organ dysfunction. A vicious cycle is set causing worsening of organ dysfunction and organ failure. With the early administration of inj. albumin, the hypotension is treated before the vicious cycle sets in thereby preventing organ dysfunction [12,13]

Although crystalloids are more widely used for fluid resuscitation than colloids of all types, the proportion of resuscitation episodes specifically using human-derived colloid solutions (i.e. albumin) has increased. [14]Albumin has been found to have a favourable safety profile and, when compared with crystalloids, is slightly more efficacious as a plasma volume-expander and less likely to reduce renal blood flow from hyperchloremia (which can occur with the use of chloride-liberal solutions like isotonic saline).[15,16] However, some studies have indicated that albumin increases costs and its impact on mortality is unclear. It is the timing of albumin treatment in sepsis/septic shock which  may be an important determinant of its utility, as early treatment with albumin has been associated with a significantly increase chance of survival.[17]

Human serum albumin (HSA) has been considered for the treatment of septic shock in initial fluid resuscitation because of its advantages of restoring effective volume and maintaining colloidal osmotic pressure. Whether albumin can improve patient-centered outcomes beyond expanding blood volume, however, is uncertain. Based on weak recommendation, the latest Surviving Sepsis Campaign guidelines suggested albumin for the initial resuscitation when patients require substantial amounts of crystalloids.

In the International Guidelines for Management of Sepsis and Septic Shock 2021, albumin was suggested to be used for patients with septic shock who receive large volumes of crystalloids, notwithstanding a “weak” recommendation strength and merely moderate quality evidence.

 Multiple studies have revealed a tendency towards improved survival rates in patients with sepsis who received albumin for the correction of hypoalbuminemia. Subgroup analysis further demonstrated reduced mortality rates among patients with septic shock.

 In our study we found that there occurred significant rise in blood pressure after 6 hours of administration of inj albumin 20%.This is attributed to the improvement of oncotic pressure after the onset of action of inj albumin.The subsequent reading after 12 hours of administration  did not show any significant change.But with 3 doses  of inj albumin as administered once a day there occurred persistence increase in blood pressure .There was significant decline in the need of vasopressors and eventually the BP was maintained without vasopressors or ionotrophs with improvement in the urine ouput by virtue of optimization of renal perfusion pressure as well.

Inj albumin 20% 100 ml if administered in early phase of septic shock ( ie within 24 hours), results in optimization of blood pressure with prevention of vicious cycle of impairment of organ perfusion and thereby prevent organ dysfunction.

1. Quinlan GJ, Martin GS, Evans TW. Albumin: biochemical properties and therapeutic potential. Hepatology2005;41:1211-1219
2. Weil MH, Henning RJ, Puri VK. Colloid oncotic pressure: clinical significance. Crit Care Med1979;7:113-116
3. Sudlow G, Birkett DJ, Wade DN. The characterization of two specific drug binding sites on human serum albumin. Mol Pharmacol1975;11:824-832
4. King TP. On the sulfhydryl group of human plasma albumin. J Biol Chem1961;236:PC5-PC5
5. Quinlan GJ, Margarson MP, Mumby S, Evans TW, Gutteridge JM. Administration of albumin to patients with sepsis syndrome: a possible beneficial role in plasma thiol repletion. Clin Sci (Lond)1998;95:459-465
6. Stamler JS, Jaraki O, Osborne J, et al. Nitric oxide circulates in mammalian plasma primarily as an S-nitroso adduct of serum albumin. Proc Natl Acad Sci U S A1992;89:7674-7677
7. Reeves RB. Temperature-induced changes in blood acid-base status: Donnan rCl and red cell volume. J Appl Physiol1976;40:762-
8. Erstad BL, Gales BJ, Rappaport WD. The use of albumin in clinical practice. Arch Intern Med1991;151:901-911
9. Cochrane Injuries Group Albumin Reviewers. Human albumin administration in critically ill patients: systematic review of randomised controlled trials. BMJ1998;317:235-240
10. Wilkes MM, Navickis RJ. Patient survival after human albumin administration: a meta-analysis of randomized, controlled trials. Ann Intern Med2001;135:149-164
11. Vincent JL, Dubois MJ, Navickis RJ, Wilkes MM. Hypoalbuminemia in acute illness: is there a rationale for intervention? A meta-analysis of cohort studies and controlled trials. Ann Surg2003;237:319-334
12. Raghunathan K, Kempker JA, Davis EA, Sindhwani NS, Telang S, Lodaya K, et al. Early Albumin Infusion Is Associated With Greater Survival to Discharge Among Patients With Sepsis/Septic Shock Who Develop Severe Acute Kidney Injury Among Patients With Sepsis/Septic Shock Who Develop Severe Acute Kidney Injury. Crit Care Explor. 2022 Dec;4(12):e0793.
13. Ye Z, Gao M, Ge C, Lin W, Zhang L, Zou Y, et al. Association between albumin infusion and septic patients with coronary heart disease: A retrospective study based on medical information mart for intensive care III database. Front Cardiovasc Med [Internet]. 2022 Oct 19 [cited 2024 Nov 11];9. Available from: https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2022.982969/full
14. SAFE Study Investigators, Finfer S, McEvoy S, Bellomo R, McArthur C, Myburgh J, et al. Impact of albumin compared to saline on organ function and mortality of patients with severe sepsis. Intensive Care Med. 2011 Jan;37(1):86–96.
15. Gabarre P, Desnos C, Morin A, Missri L, Urbina T, Bonny V, et al. Albumin versus saline infusion for sepsis-related peripheral tissue hypoperfusion: a proof-of-concept prospective study. Crit Care Lond Engl. 2024 Feb 7;28(1):43.
16. Geng L, Tian X, Gao Z, Mao A, Feng L, He C. Different Concentrations of Albumin Versus Crystalloid in Patients with Sepsis and Septic Shock: A Meta-Analysis of Randomized Clinical Trials. J Intensive Care Med. 2023 Aug;38(8):679–89.
17. Yang X, Yang L. Albumin Should Be Remembered When Patients With Septic Shock Are Resuscitated. CHEST. 2023 Sep 1;164(3):e87.