Should we initiate vasopressors earlier in patients with septic shock: A mini systemic review

Septic shock treatment remains a major challenge for intensive care units,despite the recent prominent advances in both management and outcomes.Vasopressors serve as a cornerstone of septic shock therapy,but there is still controversy over the timing of administration.Specifically,it remains unclear whether vasopressors should be used early in the course of treatment.Here,we provide a systematic review of the literature on the timing of vasopressor administration.Research was systematically identified through PubMed,Embase and Cochrane searching according to PRISMA guidelines.Fourteen studies met the eligibility criteria and were included in the review.The pathophysiological basis for early vasopressor use was classified,with the exploration on indications for the early administration of mono-vasopressors or their combination with vasopressin or angiotensinII.We found that mortality was 28.1%-47.7%in the early vasopressors group,and 33.6%-54.5%in the control group.We also investigated the issue of vasopressor responsiveness.Furthermore,we acknowledged the subsequent challenge of administration of high-dose norepinephrine via peripheral veins with early vasopressor use.Based on the literature review,we propose a possible protocol for the early initiation of vasopressors in septic shock resuscitation.

Prognosis of patients with shock receiving vasopressors

BACKGROUND:Consensus guidelines suggested that both dopamine and norepinephrine may be used,but specific doses are not recommended.The aim of this study is to determine the predictive role of vasopressors in patients with shock in intensive care unit.METHODS:One hundred and twenty-two patients,who had received vasopressors for 1 hour or more in intensive care unit(ICU) between October 2008 and October 2011,were included.There were 85 men and 37 women,with a median age of 65 years(55-73 years).Their clinical data were retrospectively collected and analyzed.RESULTS:The median simplified acute physiological score 3(SAPS 3) was 50(42-55).Multivariate analysis showed that septic shock(P=0.018,relative risk:4.094;95%confidential interval:1.274-13.156),SAPS 3 score at ICU admission(P=0.028,relative risk:1.079;95%confidential interval:1.008-1.155),and norepinephrine administration(P<0.001,relative risk:9.353;95%confidential interval:2.667-32.807) were independent predictors of ICU death.Receiver operating characteristic curve analysis demonstrated that administration of norepinephrine ≥0.7 μg/kg per minute resulted in a sensitivity of 75.9%and a specificity of 90.3%for the likelihood of ICU death.In patients who received norepinephrine ≥0.7 μg/kg per minute there was more ICU death(71.4%vs.44.8%) and in-hospital death(76.2%vs.48.3%) than in those who received norepinephrine <0.7 ug/kg per minute.These patients had also a decreased 510-day survival rate compared with those who received norepinephrine <0.7 μg/kg per minute(19.2%vs.64.2%).CONCLUSION:Septic shock,SAPS 3 score at ICU admission,and norepinephrine administration were independent predictors of ICU death for patients with shock.Patients who received norepinephrine ≥0.7 μg/kg per minute had an increased ICU mortality,an increased inhospital mortality,and a decreased 510-day survival rate.

Vasopressors in obstetric anesthesia: A current perspective

Vasopressors are routinely used to counteract hypotension after neuraxial anesthesia in Obstetrics. The understanding of the mechanism of hypotension and the choice of vasopressor has evolved over the years to a point where phenylephrine has become the preferred vasopressor. Due to the absence of definitive evidence showing absolute clinical benefit of one over the other, especially in emergency and high-risk Cesarean sections, our choice of phenylephrine over the other vasopressors like mephentermine, metaraminol, and ephedrine is guided by indirect evidence on fetalacid-base status. This review article evaluates the present day evidence on the various vasopressors used in obstetric anesthesia today.

Oral blood pressure augmenting agents for intravenous vasopressor weaning

Intravenous(IV)vasopressors are essential in the management of hypotension and shock.Initiation of oral vasoactive agents to facilitate weaning of IV vasopressors to liberate patients from the intensive care unit is common despite conflicting evidence regarding the benefits of this practice.While midodrine appears to be the most frequently studied oral vasoactive agent for this purpose,its adverse effect profile may preclude its use in certain populations.In addition,some patients may require persistent use of IV vasopressors for hypotension refractory to midodrine.The use of additional and alternative oral vasoactive agents bearing different mechanisms of action is emerging.This article provides a comprehensive review of the pharmacology,clinical uses,dosing strategies,and safety considerations of oral vasoactive agents and their application in the inten-sive care setting.

Emerging concepts in the care of patients with cirrhosis and septic shock

Septic shock impacts approximately 6% of hospitalized patients with cirrhosis and is associated with high rates of morbidity and mortality. Although a number of landmark clinical trials have paved the way for incremental improvements in the diagnosis and management of septic shock in the general population, patients with cirrhosis have largely been excluded from these studies and critical knowledge gaps continue to impact the care of these individuals. In this review,we discuss nuances in the care of patients with cirrhosis and septic shock using a pathophysiology-based approach. We illustrate that septic shock may be challenging to diagnose in this population in the context of factors such as chronic hypotension, impaired lactate metabolism, and concomitant hepatic encephalopathy. Furthermore, we demonstrate that the application of routine interventions such as intravenous fluids, vasopressors, antibiotics, and steroids should be carefully considered among those with decompensated cirrhosis in light of hemodynamic, metabolic, hormonal, and immunologic disturbances. We propose that future research should include and characterize patients with cirrhosis in a systematic manner, and clinical practice guidelines may need to be refined accordingly.

Outcomes of liver transplantation in patients with hepatorenal syndrome

Hepatorenal syndrome(HRS) plays an important role in patients with liver cirrhosis on the wait list for liver transplantation(LT). The 1 and 5-year probability of developing HRS in cirrhotic with ascites is 20% and 40%, respectively. In this article, we reviewed current concepts in HRS pathophysiology, guidelines for HRS diagnosis, effective treatment options presently available, and controversies surrounding liver alone vs simultaneous liver kidney transplant(SLKT) in transplant candidates. Many treatment options including albumin, vasoconstrictors, renal replacement therapy, and eventual LT have remained a mainstay in the treatment of HRS. Unfortunately, even after aggressive measures such as terlipressin use, the rate of recovery is less than 50% of patients. Moreover, current SLKT guidelines include:(1) estimation of glomerular filtration rate of 30 m L/min or less for 4-8 wk;(2) proteinuria > 2 g/d; or(3) biopsy proven interstitial fibrosis or glomerulosclerosis. Even with these updated criteria there is a lack of consistency regarding longterm benefits for SLKT vs LT alone. Finally, in regards to kidney dysfunction in the post-transplant setting, an estimation of glomerular filtration rate < 60 mL /min per 1.73 m2 may be associated with an increased risk of patients having long-term end stage renal disease. HRS is common in patients with cirrhosis and those on liver transplant waitlist. Prompt identification and therapy initiation in transplant candidates with HRS may improve post-transplantation outcomes. Future studies identifying optimal vasoconstrictor regimens, alternative therapies, and factors predictive of response to therapy are needed. The appropriate use of SLKT in patients with HRS remains controversial and requires further evidence by the transplant community.

Vitamin C in the critically ill-indications and controversies

Ascorbic acid(vitamin C) elicits pleiotropic effects in thebody. Among its functions, it serves as a potent antioxidant, a co-factor in collagen and catecholamine synthesis, and a modulator of immune cell biology. Furthermore, an increasing body of evidence suggests that highdose vitamin C administration improves hemodynamics, end-organ function, and may improve survival in critically ill patients. This article reviews studies that evaluate vitamin C in pre-clinical models and clinical trials with respect to its therapeutic potential.

Risk Factors for Acute Kidney Injury after Orthotopic Liver Transplantation:A Single-center Data Analysis

Acute kidney injury（AKI） is a common complication following orthotopic liver transplantation（OLT） and is associated with increased morbidity and mortality. The aim of the current study was to determine the risk factors for AKI in patients undergoing OLT. A total of 103 patients who received OLT between January 2015 and May 2016 in Tongji Hospital, China, were retrospectively analyzed. Their demographic characteristics and perioperative parameters were collected, and AKI was diagnosed using 2012 Kidney Disease： Improving Global Outcomes（KDIGO） staging criteria. It was found that the incidence of AKI was 40.8% in this cohort and AKI was significantly associated with body mass index, urine volume, operation duration（especially 〉 480 min）, and the postoperative use of vasopressors. It was concluded that relative low urine output, long operation duration, and the postoperative use of vasopressors are risk factors for AKI following OLT.

One approach to circulation and blood flow in the critical care unit

Evaluating and managing circulatory failure is one of the most challenging tasks for medical practitioners involved in critical care medicine.Understanding the applicability of some of the basic but,at the same time,complex physiological processes occurring during a state of illness is sometimes neglected and/or presented to the practitioners as point-of-care protocols to follow.Furthermore,managing hemodynamic shock has shown us that the human body is designed to fight to sustain life and that the compensatory mechanisms within organ systems are extraordinary.In this review article,we have created a minimalistic guide to the clinical information relevant when assessing critically ill patients with failing circulation.Measures such as organ blood flow,circulating volume,and hemodynamic biomarkers of shock are described.In addition,we will describe historical scientific events that led to some of our current medical practices and its validation for clinical decision making,and we present clinical advice for patient care and medical training.

Hepatorenal Syndrome

Hepatorenal syndrome (HRS) is the most serious hepatorenal disorder and one of the most difficult to treat. To date, the best treatment options are those that reverse the mechanisms underlying HRS: portal hypertension, splanchnic vasodilation, and/or renal vasoconstriction. Therefore, liver transplantation is the preferred definitive treatment option. The role of other therapies is predominantly to prolong survival sufficiently to allow patients to undergo transplantation. Terlipressin with the addition of adjunctive albumin volume expansion is the preferred pharmacologic therapy for the treatment of patients with HRS. Norepinephrine and vasopressin are acceptable alternatives in countries where terlipressin is not yet available. For patients with Type II HRS, midodrine plus octreotide appears to be an effective pharmacologic regimen that can be administered outside of an intensive care unit setting. Regardless of chosen vasoconstrictor therapy, careful monitoring is needed to ensure tissue ischemia and severe adverse effects do not occur. Artificial hepatic support devices, renal replacement therapy, and transjugular intrahepatic portosystemic shunt (TIPS) are non-pharmacologic options for patients with HRS. However, hepatic support devices and renal replacement therapies have not yet demonstrated improved outcomes and TIPS is difficult to be employed in patients with Type I HRS due to contraindications in the majority of patients. Despite advances in our understanding of hepatorenal syndrome, the disease is still associated with significant morbidity, mortality, and costs. More evidence is urgently needed to help improve patient outcomes in this difficult-to-treat population.

Critical care management and intensive care unit outcomes following cytoreductive surgery with hyperthermic intraperitoneal chemotherapy

AIM To study the early postoperative intensive care unit(ICU) management and complications in the first 2 wk of patients undergoing cytoreductive surgery(CRS) and hyperthermic intraperitoneal chemotherapy(HIPEC).METHODS Our study is a retrospective, observational study per-formed at Icahn School of Medicine at Mount Sinai, quaternary care hospital in New York City. All adult patients who underwent CRS and HIPEC between January 1, 2007 and December 31, 2012 and admitted to ICU postoperatively were studied. Fifty-one patients came to the ICU postoperatively out of 170 who underwent CRS and HIPEC therapy during the study period. Data analysis was performed using descriptive statistics.RESULTS Of the 170 patients who underwent CRS and HIPEC therapy, 51(30%) came to the ICU postoperatively. Mean ICU length of stay was 4 d(range 1-60 d) and mean APACHE Ⅱ score was 15(range 7-23). Thirtyone/fifty-one(62%) patients developed postoperative complications. Aggressive intraoperative and postoperative fluid resuscitation is required in most patients. Hypovolemia was seen in all patients and median amount of fluids required in the first 48 h was 6 L(range 1-14 L). Thirteen patients(25%) developed postoperative hypotension with seven requiring vasopressor support. The major cause of sepsis was intraabdominal, with 8(15%) developing anastomotic leaks and 5(10%) developing intraabdominal abscess. The median survival was 14 mo with 30 d mortality of 4%(2/51) and 90 d mortality of 16%(8/51). One year survival was 56.4%(28/51). Preoperative medical co morbidities, extent of surgical debulking, intraoperative blood losses, amount of intra op blood products required and total operative time are the factors to be considered while deciding ICU vs non ICU admission.CONCLUSION Overall, ICU outcomes of this study population are excellent. Triage of these patients should consider preoperative and intraoperative factors. Intensivists should be vigilant to aggressive postop fluid resuscitation, pain control and early detection and management of surgical complications.

Multicentered prospective investigator initiated study to evaluate the clinical outcomes with extracorporeal cytokine adsorption device (CytoSorb®) in patients with sepsis and septic shock

BACKGROUND Sepsis is a severe clinical syndrome related to the host response to infection.The severity of infections is due to an activation cascade that will lead to an auto amplifying cytokine production:The cytokine storm.Hemoadsorption by CytoSorb®therapy is a new technology that helps to address the cytokine storm and to regain control over various inflammatory conditions.AIM To evaluate prospectively CytoSorb®therapy used as an adjunctive therapy along with standard of care in septic patients admitted to intensive care unit(ICU).METHODS This was a prospective,real time,investigator initiated,observational multicenter study conducted in patients admitted to the ICU with sepsis and septic shock.The improvement of mean arterial pressure and reduction of vasopressor needs were evaluated as primary outcome.The change in laboratory parameters,sepsis scores[acute physiology and chronic health evaluation(APACHE II)and sequential organ failure assessment(SOFA)]and vital parameters were considered as secondary outcome.The outcomes were also evaluated in the survivor and nonsurvivor group.Descriptive statistics were used;a P value<0.05 was considered RESULTS Overall,45 patients aged≥18 and≤80 years were included;the majority were men(n=31;69.0%),with mean age 47.16±14.11 years.Post CytoSorb®therapy,26 patients survived and 3 patients were lost to follow-up.In the survivor group,the percentage dose reduction in vasopressor was norepinephrine(51.4%),epinephrine(69.4%)and vasopressin(13.9%).A reduction in interleukin-6 levels(52.3%)was observed in the survivor group.Platelet count improved to 30.1%(P=0.2938),and total lung capacity count significantly reduced by 33%(P<0.0001).Serum creatinine and serum lactate were reduced by 33.3%(P=0.0190)and 39.4%(P=0.0120),respectively.The mean APACHE II score was 25.46±2.91 and SOFA scores was 12.90±4.02 before initiation of CytoSorb®therapy,and they were reduced significantly post therapy(APACHE II 20.1±2.47;P<0.0001 and SOFA 9.04±3.00;P=0.0003)in the survivor group.The predicted mortality in our patient population before CytoSorb®therapy was 56.5%,and it was reduced to 48.8%(actual mortality)after CytoSorb®therapy.We reported 75%survival rate in patients given treatment in<24 h of ICU admission and 68%survival rates in patients given treatment within 24-48 h of ICU admission.In the survivor group,the average number of days spent in the ICU was 4.44±1.66 d;while in the nonsurvivor group,the average number of days spent in ICU was 8.5±15.9 d.CytoSorb®therapy was safe and well tolerated with no adverse events reported.CONCLUSION CytoSorb®might be an effective adjuvant therapy in stabilizing sepsis and septic shock patients.However,it is advisable to start the therapy at an early stage(preferably within 24 h after onset of septic shock).

Progesterone Receptor Antagonists-A Novel Treatment for Severe Hyponatremia from the Endocrine Paraneoplastic Syndrome

Hyponatremia related to ectopic secretion of cancer cells of arginine vasopressin(AVP)or atrial natriuretic peptide(ANP)is most commonly caused by small cell lung cancer.The ideal treatment would be one that not only corrects the hyponatremia,especially if it is life threatening,but at the same time causes regression of the cancer,and thus improves both quality and length of life.As one is waiting for chemotherapy,surgery,or radiotherapy to decrease the cancer burden,tolvaptan has been used to correct the hyponatremia to improve symptoms or prevent death.Mifepristone,a progesterone receptor modulator/antagonist has been used to treat various cancers.The oral 200mg tablet was given to an 80-year-old woman who developed sudden extensive lung cancer with a serum sodium of 118 mmol/L.She refused chemotherapy but agreed to take mifepristone.The hyponatremia was completely corrected(145 mmol/L)within one month of treatment.She was in complete remission for 5 years and died not from lung cancer,but an acute myocardial infarction.Mifepristone may serve the purpose to not only quickly correct hyponatremia when it is related to an endocrine paraneoplastic syndrome,but also to provide improved quality and length of life.

Vasopressin use in critically ill cirrhosis patients with catecholamine-resistant septic shock: The CVICU cohort

AIM To examine patient-centered outcomes with vasopressin(AVP) use in patients with cirrhosis with catecholaminerefractory septic shock. METHODS We conducted a single center, retrospective cohort study enrolling adult patients with cirrhosis treated for catecholamine-resistant septic shock in the intensive care unit(ICU) from March 2011 through December 2013. Other etiologies of shock were excluded. Multivariable regression models were constructed for seven and 28-d mortality comparing AVP as a second-line therapy to a group of all other vasoactive agents. RESULTS Forty-five consecutive patients with cirrhosis were treated for catecholamine-resistant septic shock; 21 received AVP while the remaining 24 received another agent [phenylephrine(10), dopamine(6), norepinephrine(4), dobutamine(2), milrinone(2)]. In general,no significant differences in baseline demographics, etiology of cirrhosis, laboratory values, vital signs or ICU mortality/severity of illness scores were observed with the exception of higher MELD scores in the AVP group(32.4, 95%CI: 28.6-36.2 vs 27.1, 95%CI: 23.6-30.6, P = 0.041). No statistically significant difference was observed in unadjusted 7-d(52.4% AVP vs 58.3% and P = 0.408) or 28-d mortality(81.0% AVP vs 87.5% non-AVP, P = 0.371). Corticosteroid administration was associated with lower 28-d mortality(HR = 0.37, 95%CI: 0.16-0.86, P = 0.021) independent of AVP use. CONCLUSION AVP is similar in terms of patient centered outcomes of seven and 28-d mortality, in comparison to all other vasopressors when used as a second line vasoactive agent in catecholamine resistant septic shock. Large-scale prospective study would help to refine current consensus standards and provide further support to our findings.

Central venous pressure value can assist in adjusting norepinephrine dosage after the initial resuscitation of septic shock

Background: New definitions for sepsis and septic shock (Sepsis-3) were published, but the strategy to adjust vasopressors a initial guidelines is still unclear. We conducted a retrospective observational study to explore dosing strategy of norepinephrine (NE). Methods: A retrospective observational study in the 15-bed mixed intensive care unit of a tertiary care university hospital. The study was performed on septic shock patients after 30 mL/kg fluid resuscitation and mean arterial pressure (MAP) levels reached >65 mmHg requiring NE. We divided patients into NE dosage increase and decrease groups, and collected hemodynamic and tissue perfusion parameters before (Tl) and after (T2) adjusting NE dosage. Results: In both NE increase and decrease groups, central venous pressure (CVP) and pressure difference between usual MAP and MAP (dMAP) at the T1 time point were associated with lactate clearance. In groups LC HM (CVP <10mmHg, dMAP〉OmmHg) and HC HM (CVP > 10 mmHg, dMAP > 0 mmHg), decrease in NE dosage decreased lactate level, while in group HC LM (CVP >10 mmHg, dMAP < 0 mmHg), both increase and decrease in NE dosage led to increase lactate level. Conclusions: After patients with septic shock (Sepsis-3) resuscitated to reach the initial recovery target goals, combination of CVP and MAP refer to usual levels can help doctors make the next decision to make the correct choice of increase NE dosage or decrease NE dosage.

Alternatives to norepinephrine in septic shock:Which agents and when?

Vasopressors are the cornerstone of hemodynamic management in patients with septic shock.Norepinephrine is currently recommended as the first-line vasopressor in these patients.In addition to norepinephrine,there are many other potent vasopressors with specific properties and/or advantages that act on vessels through different pathways after activation of specific receptors;these could be of interest in patients with septic shock.Dopamine is no longer recommended in patients with septic shock because its use is associated with a higher rate of cardiac arrhythmias without any benefit in terms of mortality or organ dysfunction.Epinephrine is currently considered as a second-line vasopressor therapy,because of the higher rate of associated metabolic and cardiac adverse effects compared with norepinephrine;however,it may be considered in settings where norepinephrine is un-available or in patients with refractory septic shock and myocardial dysfunction.Owing to its potential effects on mortality and renal function and its norepinephrine-sparing effect,vasopressin is recommended as second-line vasopressor therapy instead of norepinephrine dose escalation in patients with septic shock and persistent arterial hypotension.However,two synthetic analogs of vasopressin,namely,terlipressin and selepressin,have not yet been employed in the management of patients with septic shock,as their use is associated with a higher rate of digital ischemia.Finally,angiotensin II also appears to be a promising vasopressor in patients with septic shock,especially in the most severe cases and/or in patients with acute kidney injury requiring renal replacement therapy.Nevertheless,due to limited evidence and concerns regarding safety(which remains unclear because of potential adverse effects related to its marked vasopressor activity),angiotensin II is currently not recommended in patients with septic shock.Further studies are needed to better define the role of these vasopressors in the management of these patients.