Management of sepsis in a cirrhotic patient admitted to the intensive care unit: A systematic literature review

Table 1 Summary of randomized controlled trials

Ref.	Purpose	Type of study	Sample size	Conclusion	Setting
Philips et al[11]	Assessed the use of 5% human fluid for the resuscitation of cirrhotic patients with sepsis		Three hundred-eight patients were divided into two groups	5% human albumin was safe and more beneficial in correcting hypotension than normal saline	ICU
Arabi et al[13]	Assess the use of a low dose of hydrocortisone in cirrhotic patients with sepsis	RCT	140 patients were 65 excluded, and 39 received hydrocortisone and 36 placeboes	That study did not find mortality improvement with corticosteroids despite hemodynamic improvement. The treatment proposed: Hemodynamic monitoring and management, laboratory test culture, stress ulcer prophylaxis as histamine H2 receptor antagonists, norepinephrine as vasopressors, and empiric antibiotic. The outcome was 28 days of all-cause mortality	ICU

RCT: Randomized controlled trial; ICU: Intensive care unit.

Table 2 Prospective cohort studies

Ref.	Purpose	Type of study	Sample size	Conclusion	Setting
Rinaldi et al[5]	The aim was to evaluate the effect of adherence to evidence-based guidelines of the Surviving Sepsis Campaign (SSC) on the outcome of cirrhotic patients with shock admitted to the ICU. Resuscitation of sepsis with hydrocortisone	Prospective cohort	38 patients		ICU
Thierry et al[23]	Assess the use of echocardiography in assessing the LVEF on cirrhotic patients with septic shock	The prospective cohort single-center study	34 patients compared	Echocardiography in a cirrhotic patient with septic shock show hyperdynamic syndrome with high LVEF	ICU

SSC: Surviving sepsis campaign; ICU: Intensive care unit; LVEF: Left ventricle ejection function.

Table 3 Retrospective cohort studies

Ref.	Purpose	Type of study	Sample size	Conclusion	Setting
Guo et al[26]	Assessment of VCS parameter for evaluation of sepsis in cirrhotic patients	Retrospective analysis of prospective data	257 patients	Proposed management was collection of blood culture, white cell volume determination, procalcitonin, and interleukin -6, sCD163 laboratory tests. Conclusion VCS parameters have the potential to be used to evaluate and predict early infections in patients with cirrhosis, and VCS can increase sensitivity and specificity in the diagnosis of sepsis and cirrhosis patients	ICU
Villarreal et al[15]	Assessing the usefulness of procalcitonin for diagnosing infection in cirrhotic patients	Retrospective cohort study	66 patients of 255 admitted had procalcitonin tests. Patients with infection suspicion had a serum procalcitonin (PCT) test within the first 12 h	Septic patients with cirrhosis had elevated procalcitonin. As PCT has a sensitivity of 83% and specificity of 75% is an effective tool for diagnosing infection in patients with liver cirrhosis. Excellent tool for differentiating infectious disease in cirrhotic patients	ICU
Galbois et al[27]	Assess whether the mottling score and tissue oxygen saturation (StO2) may be used as early death predictors on cirrhotic patients with septic shock. Hemodynamic parameters at 6 h in patients with liver cirrhosis according to their survival status at 14 days	42 out of 46 patients admitted with cirrhosis and septic shock were analyzed		There is systemic vasodilation and increased mortality in cirrhosis patients with sepsis. Patients with increased mottling died, and those with decreased survived. Mottling score and knee StO2 measures 6 h after starting vasopressors are excellent predictors of 14-day mortality	ICU
Piccolo Serafim et al[14]	The study evaluates the use of steroids in a patient with septic shock and cirrhosis	A retrospective cohort study (2007-2017)	56 patients out of 179 admitted with septic shock received steroids during ICU	The use of steroids did not show significant differences in mortality. Vasopressor requirement and is not associated with decreased mortality	ICU
Chang et al[17]	aimed to determine whether septic patients with liver cirrhosis had worse survival than patients without liver cirrhosis	Retrospective cohort	776 patients, 64 had sepsis with cirrhosis, 712 sepsis without cirrhosis	Cirrhotic patients with sepsis had a poor outcome, and the survival of sepsis and cirrhosis after matching was not inferior to those without cirrhosis	ICU
Sauneuf et al[18]	Assess the use of albumin as an adjuvant to vasopressors in managing septic shock in cirrhotic patients	Retrospective cohort single center and observational overdone over 14 years studied done from 1997 to 2004 and 2005 to 2010	During the period 2005 to 2010, 42, cirrhotic patients with septic shock in ICU were included	In conclusion, the survival rate of septic shock in cirrhosis remains low, and current shock management could benefit cirrhotic patients. Treatment use is: Vasopressors used is norepinephrine, epinephrine, and dobutamine; mechanical ventilation was used in the case of ARDS, and a protective strategy with a low tidal volume of 6 m/kg of body weight, and the plateau was kept below 30 cmH2O, small -dose of corticosteroids (200 mg hydrocortisone per day, insulin therapy, The main sites of infections were: Pneumonia, spontaneous or secondary peritonitis, and urinary tract infection. There were gram-positive and negative. Septic shock represent a severe complication of cirrhosis with very low survival rates. Sepsis in a cirrhotic patient has a poor prognosis. Hydrocortisone did not reduce mortality and was associated with adverse effects such as shock relapse and gastrointestinal bleeding. Cirrhotic patients are commonly perceived as poor candidates for `ICU admission because of the very high mortality	ICU
Umgelter et al[21]	Assess the outcome of the continuous low dose of TP in a septic shock patient	Small cohort study	2004-2007: 12 patients, 8 males, and 4 females were included with sepsis due to spontaneous bacterial peritonitis, pneumonia, and cholangitis	TP is currently used in treating cirrhotic patients with hepatorenal syndrome and as an adjunct to NE in a cirrhotic patient with septic shock and kidney failure; TP dose 2 ug/kg if a patient was started NE in the first 24 h. 11 patients had RRT, TP increased SVR index and NE doses needed to obtain target MAP decreased while the CI remained stable. Despite hemodynamic improvement, 11 out of 12 patients died. The author concluded that TP was effective as a vasopressor in septic cirrhotic patients at a low dose in combination with NE, and there was no dramatic decrease in CI. TP has a role in the early treatment of septic shock, and the author recommends a controlled study with TP in a cirrhotic patient with sepsis	ICU
Durst et al[20]	The study aimed to evaluate the use of vasopressor in septic shock with cirrhosis and without cirrhosis	single-center, retrospective cohort, 18 years	122 patients included were 61 with cirrhosis and 61 non-cirrhosis with sepsis, and septic with cirrhosis		ICU
Maimone et al[12]	Compare the 20% albumin to plasmolytes in managing cirrhosis and sepsis in the intensive care unit	Retrospective cohort study	100 patients with cirrhosis and sepsis-induced hypotension		ICU
Bal et al[24]	The aim is to predict 50 days in hospital mortality in decomposed cirrhosis patients with SBP	A single-centre study prospective study	218 were admitted to ICU from 2013-2014 with cirrhosis and spontaneous bacterial peritonitis		ICU
Chebl et al[22]	Assess the outcome and mortality predictor of cirrhosis patients with sepsis	A single-center retrospective cohort study	200 patients	The study revealed an increased risk of sepsis in cirrhotic patients and sepsis-induced organ failure and related death in cirrhosis. The management of shock is to keep MAP above 65 mmgh with vasopressors; the aggressive fluid hydration may worsen the outcome as there is low oncotic pressure in a cirrhotic patient, which may lead to oedema with aggressive fluid hydration, so it is good to start with vasopressors early in the treatment of septic cirrhosis patients to avoid complications, a cirrhotic patient has higher lactate than the non-cirrhotic because of decreased lactate clearance by the liver	ICU
Chen et al[25]		A single-center, retrospective cohort study from 2015 to 2018	104 patients with cirrhosis and bacteremia were subdivided into afebrile (55) and febrile (49)	The cirrhotic patient is prone to infection. Cirrhotic patients with bacterial infections present with atypical manifestations such as normothermia. Scoring systems focused on organ dysfunction, such as quick sequential organ failure assessment (qSOFA) score or chronic liver failure sequential organ failure assessment (CLIF-SOFA) score, have better predictor ability	In the emergency department
Sasso et al[19]	Assess the prediction of mortality in a cirrhotic patient	Prospective cohort	113 patients mechanically ventilator cirrhotic from 2014-2018	Conclude that cirrhotic patients requiring mechanical ventilation have an extremely poor prognosis, and the vasopressor requirement was strongly a predictor of mortality in mechanical ventilation cirrhosis with sepsis	ICU
Fischer et al[12]	Assess the use of presepsin and resistin as markers of bacterial infections in cirrhotic patients with sepsis			Conclusion: Both presepsin and resistin may be reliable markers of bacterial infections in patients with decompensated liver cirrhosis and have similar diagnostic performance for bacterial infection and sepsis compared to C-reactive protein (CRP) and PCT. The best cut-off level of presepsin for diagnosis of sepsis was 1444 pg/mL. Conclusion PCT, CRP, Presepsin, and resistin had similar accuracy in diagnosing infection and sepsis in decompensated cirrhosis	ICU
Baudry et al[9]	Assess the prognosis of sepsis in cirrhotic patients	A Retrospective cohort study from 2002-2013	7644 patients were admitted, where 149 were		ICU

VCS: Value of volume conductivity and scattering; PCT: Procalcitonin; STO₂: Tissue oxygen saturation; ARDS: Acute respiratory distress syndrome; TP: Telipressin; NE: Norepinephrine; SVR: Systemic vascular resistance; RRT: Renal replacement therapy MAP: Mean arterial pressure; CI: Cardiac index, ATB: Antibiotic; MELD: Model for End-Stage Liver Disease; AKI: Acute kidney injury; SBP: Systolic blood pressure; qSOFA: Quick sequential organ failure assessment; ICU: Intensive care unit.

Table 4 Summary of selected studies

Ref.	Year	Aim	Setting	Results	Conclusion
Philips et al[11]	2021	Assessed the use of 5% human fluid for the resuscitation of cirrhotic patients with sepsis	ICU	Found that primary, the two groups were different, with P values of less than 0.05, which is statistically significant. Study was done among 300 patients with sepsis with hypotension and cirrhosis 123 (n = 154, 79.8% receive albumin, and 131 (154, 85.1%) receive normal saline. Outcome related to MAP. measurement only 7.5 (n = 23) show reversal hypotension MAP > 65 at the end of the first hours of the resuscitation period; after 3 h, it was 11.7% (n = 18) and 32% (n = 5) in albumin and saline groups respectively (P = 0.008); Secondary outcome related to MAP, in the first hours while the study group, 62 patients (20.1%, n = 308) fluid resuscitation and sustained at 2 h in 42 (13.6%) patients improved MAP more than 65 mmHgf was seen in 25.3 (n = 39). In the albumin group at the end of the first hour compared to 14.9% (n = 23) patients in the saline group (P = 0.03). In second hour 17.5% (n = 27) in albumin group compare 9.7% (in = 15, P = 0.06) in saline group 5% albumin showed better improvement of MAP hemodynamic response compared to saline with P < 0.001 that is statistically significant. First hour, HA vs NS: 99.5 ± 7.9 vs 101.7 ± 8.8, P = 0.02; Second hour 97.9 ± 5.5 vs 103.4 ± 6.7, P < 0.001); Third hour 96.6 ± 3.6 vs 103.1 ± 5.9, P < 0.001	Found 5% human albumin correcting hypotension in sepsis with cirrhosis patients. Data were analyzed using IBM SPSS 22.0 statistic window. Quantitative variables were presented as mean ± SD and presented as number and percentage, the Chi-square or Fischer's exact test was used for categorical data, and continuous data were analyzed using the students' test or Mann-Whitney U test, Kaplan-Meier used for survival curves
Arabi et al[13]	2010	Assess the use of a low dose of hydrocortisone in cirrhotic patients with sepsis	ICU	140 patients screened 75 enrolled in the study. 60 (80%) with shock within 24 h and 71 (95%) with shock within 48 h. Twenty-eight days mortality with hydrocortisone treatment compared to its placebo 33 (85%) vs 26 (72%) relative risk (RR) 1.17, 95% confidence interval 0.92-1.49, P = 0.19). There was relative adrenal insufficiency in cirrhosis patients presenting with septic shock. Hydrocortisone show significant hemodynamic improvement. The 28-day mortality 33 (85) P = 0.19 and ICU mortality 24 (62) P = 0.64. Hemodynamic response was shock reversal 24 (62) P = 0.05 statistically significant	Found that corticosteroids improve hemodynamic status of the patient but do not change mortality
Rinaldi et al[5]	2013	The aim was to evaluate the effect of adherence to evidence-based guidelines of the surviving sepsis campaign (SSC) on the outcome of cirrhotic patients with shock admitted to the ICU	ICU	30 day-mortality of cirrhotic patients with septic shock in ICU is extremely high, and the application of SSC guidelines did not seem to improve the survival rate in this population. In addition, approximately 40% of cirrhotic patients developed an infection. 30 days mortality of 31 (81.6%) patients, 13 (86.6) with the bundle completed and 18 (78.2%) with the bundle not completed. This difference was not statistically significant	Hydrocortisone was associated with shock resolution but no survival modification. Chang et al[17], (2022) show that sepsis in cirrhotic patients has poor outcome than sepsis without Cirrhosis. And Sauneuf et al[18], (2013) found also that sepsis in cirrhotic patient survival remain low despite current management. Bal et al[24], 2016 found that mortality in 50 days in septic with cirrhosis patients was 43%
Thierry et al[23]	2007	Assess the use of echocardiography in assessing the LVEF on cirrhotic patients with septic shock	ICU	Show clinical and echocardiographic hemodynamic parameters between patients with Cirrhosis and without Cirrhosis; Cirrhosis had higher. Without Cirrhosis, Cirrhosis had higher values for the CI (3.69+/-1 vs 2.86+/-0.81/min/m2, P = 0.02. SI (37.5 ± 8 vs 32.4 ± 7 mL/m2, P = 0.04); LVEF (67 ± 7 vs 55.9 ± 12%, P = 0.005 and lower value for the SVR (1636.1 ± 523 vs 2136.6+/-633 dynes/cm5 m2, P = 0.04). The MELD score was not significantly correlated with the CI (R = 0.20, P = 0.49, or S (r = 0.15, P = 0.6). Mortality in ICU was 53% overall (64% vs 45%, P = 0.27), not statistically different from the patient without Cirrhosis	Show that echocardiography is of important help in the management of Cirrhosis with sepsis, showing hyperdynamic syndrome with high LVEF
Guo et al[26]	2019	Assessment of VCS parameter for evaluation of sepsis in cirrhotic patients	ICU	52% of positive culture in septic patients with Cirrhosis, with traditional infection markers (PCT, IL-6) and sCD163 between the two groups significantly different (P < 0.001). VCS parameters WBC range from 1.4 to 18.3 in sepsis, and leucocytes range from 1.6 to 19.2 in patients with infection no difference in the two groups for WBC. Test sensitivity was 75.9%, and a specificity of 73% was achieved	Reviewed the management of cirrhosis patients with sepsis and proposed: Blood vulture collection, white cell volume determination, procalcitonin and interleukin -6 and sCD163 test, and he concluded that VCS parameters predict the presence of infection early in cirrhotic patients
Villareal et al[15]	2016	Assessing the usefulness of procalcitonin for diagnosing infection in cirrhotic patients	ICU	Found that the mean scores as mean child-Pugh score 9.5 ± 2 and MELD score 23 ± 8 with P = 0.14 and P = 0.33, respectively, and there were not statistically significant for Cirrhosis with and without infection, and the mortality was high 62.9%. Procalcitonin (PCT) as biomarkers was found to be higher in a patient with infection than those without infection 4.20 (1.4-10.2) vs 0.16 (0.1-0.23) through statistically significant differences were not reached P = 0.53, severe sepsis or septic shock was associated with higher PCT	Procalcitonin as biomarker might help with infection diagnosis in cirrhotic patients, and P. Fischer et al. (2019) found that both presepsin and resistin may be reliable markers of bacterial infection in patients with decompensated liver cirrhosis and have similar diagnostic performance compared to PCT
Chen et al[25]	2019		ICU	Find that the mean time of initiation of the antibiotic treatment was 3.5 h in the patient (afebrile: 4.3 h, febrile 2.8 h P = 0.23 high incidence of the afebrile group admitted in ICU (43.6% vs 20.4% P = 0.01) and higher 30 days mortality in afebrile group 40% vs 18.4%) P = 0.02) and endotracheal intubation 27.3% vs 10.2%, P = 0.03) infection	Found that the cirrhotic patient has an atypical presentation, and the qSOFA score or CLIF-SOFA score has a better predictor ability
Umgelter et al[21]	2008	Assess the outcome of the continuous low dose of terlipressin (TP) in a septic shock patient	ICU	Find that ICU admission patients had a mean age of 58 ± 85 mean Child-Pugh score of 13.8 ± 0.8, and a mean APACHE ii score of 31 ± 6 where TP decreases systemic vascular resistance index and norepinephrine (NE) doses needed to obtain the target MAP decreased, while cardiac index CI remained stable, median survival after initiating TP was ranging 5-15 days	Found that TP at a dose of 2 ug/kg can be used as an adjunct to NE in a cirrhotic patient with sepsis for hemodynamic improvement
Durst et al[20]	2021	The study aimed to evaluate the use of vasopressor in septic shock with cirrhosis and without cirrhosis	ICU	state that sepsis in cirrhosis was more likely to occur than in non-cirrhotic 34 (55.7%) versus 23(37.8%), P = 0.046, and received steroid 38.3% and 19.7%, respectively P = 0.024. The cirrhosis group requires increased median (IQR) total vasopressor dosage when compared to non-cirrhotic [71.5 (15.5-239.5)] vs 24.7 (5.3-77.9) mg NE equivalent, P = 0.003 and required a significantly higher total number of vasopressor agents 3 (1-4) vs 2 (1-3) agents P = 0.03. The length of ICU stays 7.0 (3.6-11.4) vs 5.0 (2.6-10.4) days P = 0.146 no statistically significant and MAP goal greater than baseline BP was 3 (4.9%)	Found that for sepsis and Cirrhosis needing vasopressors, MAP should be maintained above 60 mmgh, and blood culture and antibiotic should be started early as a survival campaign guideline
Galbois et al[27]	2015	Assessment of VCS parameter for evaluation of sepsis in cirrhotic patients	ICU	Found that cirrhosis patients with sepsis admitted to ICU were child-Pugh c without mottling, and mortality at 14 days was 71% (at day 28:78% in ICU: 76% in hospital: 82%). Hemodynamic parameters at 6 h were: MAP more than 65mmgh that was 88%, CVP more than 8mmgh: was 90%, ScvO2 more than 81%, Urine output more than 0.5 mL/kg/h: 24%. Thenar and knee Sto2 at H6 to predict the outcome. Thenar Sto2 levels measured at H0 and H6 were not different in survivors and non-survivors. [H0: 77% (72-87) vs 84% (79-90), P = 0.11, H6:84% (79-89) vs 83% (71-92), P = 0.89]. Mottling score changes during the first 24 h of septic shock in a patient with and without Cirrhosis; in survivors, the proportion of patients with a mottling score of more than 2 decreased over time in both groups. in non-survivors, the proportion of patients with severe mottling score (4-5) increased over time in both groups. In non-survivors, the proportion of patients with a mottling score (0-1) was higher in patients with Cirrhosis than in patients without at H0 P = 0.001) and at H6 (P = 0.02), but was not significantly later	Described that mottling score and knee StO2 measurement at 6 h after vasopressors have excellent 14 days mortality prediction
Piccolo Serafim et al[14]	2021	The study evaluates the use of steroids in a patient with septic shock and Cirrhosis	ICU	Found that patients who received steroids received a higher total of vasopressors (91.2 mg vs 39.1 mg, P = 0.04) and lower of lactate (1.8 mmol/L vs 2.6 mmol/L, P = 0.007)	Show that steroids did not improve mortality despite hemodynamic changes
Chebl et al[22]	2021	Assess the outcome and mortality predictor of cirrhosis patients with sepsis	ICU	found that cirrhotic patients were more likely to get intubated than non-cirrhotic patients (72.49% vs 61.62%, P = 0.001), and there was no statistically significant difference in mechanical ventilation duration or ICU LOS among survivors. Cirrhotic patients have higher hospital mortality than non-cirrhotic patients (64.79% vs 31.54% P = 0.001) and higher ICU mortality (47.47% vs 18.05% P = 0.001)	proposed as management of cirrhotic patient with sepsis to keep MAP > 65 mmgh with vasopressors, and start vasopressors early because of reduced oncotic pressure and risk of pulmonary oedema, avoid aggressive fluid resuscitation, cirrhotic patients have higher lactate levels
Maimone et al[12]	2022	Compare the 20% albumin to plasmolytes in managing Cirrhosis and sepsis in the intensive care unit.	ICU	Found that sepsis and septic shock in cirrhotic patient was the leading cause of acute decompensation or acute, chronic liver failure and had a poor prognosis and increased mortality	Show that albumin 20% increases MAP above 65 mmgh 3 h after infusion compared with plasmolyte and restores hemodynamic status rapidly but induce pulmonary oedema; why is it important to close monitoring with ultrasound so early detection of pulmonary oedema and management
Bal et al[24]	2013	The aim is to predict 50 days in hospital mortality in decomposed cirrhosis patients with SBP	ICU	Bal et al[24] study show that 50 days mortality in ICU was 43.11% of the patient admitted	Show that patients admitted to intensive care units with sepsis and Cirrhosis have poor prognoses and are a poor candidate for ICU
Baudry et al[9]	2019	Assess the prognosis of sepsis in cirrhotic patients.	ICU
Sauneuf et al[18]	2013	Assess the use of albumin as an adjuvant to vasopressors in managing septic shock in cirrhotic patients.	ICU	Find from 2005 to 2010, 40.5% were discharged from ICU, and 26% were alive six months after discharge. IV albumin was frequently given (57.1% vs 8.5%, P < 0.001), and crystalloid infusion was reduced at the same time [3 (1.7-4.5) L vs 6 (3-8,9) L, P = 0.08]. The ventilatory management with a smaller tidal volume 8.6 vs 7ml/kg, P = 0.001). Intensive insulin therapy and low-dose glucocorticoids were also used frequently during the second period, 83.3% vs 31.9% P < 0.001 and 81% vs 44.7, P < 0.001, respectively. Marked survival improvement in ICU as compared 1997-2004 period (40% vs 17%, P = 0.02, and 29% vs 6%, P = 0.009, respectively)
Sasso et al[19]	2020	Assess the Prediction of mortality in a cirrhotic patient	ICU	Study shows changes in SOFA score median (IQR) in a cirrhotic patient. 24 h post admission 2.5 (0.75 to 5, P = 0.122 and 48 h post admission 1(0 to 4) P = 0.269. End of vasopressor therapy 0 (-3.5 to 21, P = 0.963, that is not statistically significant. But the duration of vasopressor in (hour) median (IQR) 86 (42.0-164.5) P = 0.003. MAP goal decreased during vasopressor course n (%) 13 (21.3) P = 0.041 statistically significant	Concluded that mechanically ventilated cirrhotic patients with sepsis have an extremely poor prognosis, and vasopressor use was strongly a predictor of mortality
Chang et al[17]	(2022)	The study aimed to determine whether septic patients with liver cirrhosis had worse survival than patients without liver cirrhosis	ICU	Found that liver cirrhosis was more common in male patients with 48% median range APACHE II was 25.5%, 27% of ICU mortality, sepsis with compensated liver cirrhosis mechanical ventilation 24% P value 0.179 and 4% (P = 0.842) needed for renal replacement therapy
Fischer et al[16]	2019	Assess the use of presepsin and resistin as markers of bacterial infections in cirrhotic patients with sepsis	ICU	Found that 63% of the aetiology of Cirrhosis was alcoholism, 46% was bacterial infection (SBP), as infection markers presepsin, resistin, CRP, and PCT for predicting 28 days survival were AUROC = 0.74 (95% VI: 0.64-0.84) (P < 0.001), 0.68 (95%CI: 0.57-0.82) (P = 0.006, 0.74 (95%CI: 0.64-0.84)(P < 0.001) and 0.70 (95%CI: 0.59-0.81) (P = 0.001) respectively

CI: Confidence interval; ICU: Intensive care unit; IL-6: Interleukin 6; LVEF: Left ventricle ejection function; MAP: Mean arterial pressure; MELD: Model for End-Stage Liver Disease; NE: Norepinephrine; PCT: Procalcitonin; qSOFA: Quick sequential organ failure assessment; RR: Relative risk; SBP: Systolic blood pressure; SSC: Surviving sepsis campaign; TP: Terlipressin; VCS: Value of volume conductivity and scattering; WBC: White blood cell.