Figure 1 - uploaded by Lakhmir S Chawla
Content may be subject to copyright.
Study drug titration protocol. NorEpi, norepinephrine; MAP, mean arterial pressure. 

Study drug titration protocol. NorEpi, norepinephrine; MAP, mean arterial pressure. 

Source publication
Article
Full-text available
IntroductionPatients with distributive shock who require high dose vasopressors have a high mortality. Angiotensin II (ATII) may prove useful in patients who remain hypotensive despite catecholamine and vasopressin therapy. The appropriate dose of parenteral angiotensin II for shock is unknown.Methods In total, 20 patients with distributive shock a...

Contexts in source publication

Context 1
... being titrated off. As hypertension is not part of our standard of care, the investigators halted the infusion, and the ATII was weaned off. In both cases the need for norepinephrine was rapidly re-established. Pre- clinical studies demonstrate that animals that become septic after pre-treatment with enalapril are resistant to norepinephrine as a vasopressor [17]. Based on these findings, we hypothesized that the two patients who were very sensitive to ATII may have been receiving an angiotensin-converting enzyme inhibitor prior to develop- ing septic shock, thus, explaining the exquisite sensitivity to ATII infusion. However, a detailed chart review re- vealed incomplete information, and we were unable to document pre-morbid exposure to angiotensin- converting enzyme inhibitor. Therefore, the ATII sensitivity that we observed could be due to other mechanisms that have not been elucidated. We observed that ATII may have synergy with other vasopressors (that is, catecholamines and vasopressin), but may also have another important indication in critically ill patients. Previous work in pre-clinical studies sug- gests that septic animals suffer acute kidney injury in part due to intra-glomerular hypotension induced by efferent arteriole vasodilation. In these models, intravenous infusion with ATII restores creatinine clearance and urine output [18]. While the present study was underpowered to elucidate any effect on urine output, we expect further large-scale studies will clarify the effect of ATII on kidney function in high-output shock. In addition, ATII is a potent vasopressor without inotropic or chronotropic properties [19]. Recent randomized controlled trials in patients with septic shock treated with norepinephrine suggest that less chronotropy may be desirable and may lead to a survival benefit [4]. Based on these findings, for patients who require norepinephrine and are tachycardic, ATII may be particularly useful. We hypothesize that for patients with severe hypotension, lower doses of multiple vasopressors with differing mechanisms of action may be more efficacious and less toxic than high doses of one type of vasopressor (that is, catecholamines). The study had multiple strengths. First, the study was a randomized double-blind controlled trial with an appropriate placebo-control arm. Second, it was of prag- matic design, as it was the intent of the investigators to enroll patients receiving standard-of-care treatment for high-output shock. As such, all patients had received a priori appropriate monitoring and therapeutic interventions (including central venous lines, bladder catheters, arterial lines, and cardiac output monitoring devices). There was no additional need for any specialized equip- ment of procedures prior to enrollment in the study. Third, all enrolled patients had a documented need for high-dose vasopressor therapy despite volume therapy, as evidenced by the cardiac index entry criteria. This, we believe, is in keeping with the current practice of ad- dressing volume responsiveness in a hypotensive patient prior to initiation of vasopressor therapy. Finally, as part of our study protocol, we employed the use of a data safety monitor, who had the ability to unblind data and evaluate for adverse events as well as halt the study, nei- ther of which occurred. The study had several limitations. First, the study had a modest sample size. As such, we were unable to make conclusions about the effect of ATII on urine output due to the high incidence of oliguria and renal replace- ment therapy in both the ATII group and the placebo group. Moreover, this study was not powered adequately to discern a difference in mortality between the ATII and placebo groups. Second, there were some imbalances between our placebo arm and our drug arm, the former of which were younger, but sicker (according to both SOFA and APACHE II scores). It is possible that differences in these two populations influenced the effectiveness of ATII. Finally, inclusion criteria for enrollment in the study were such that the resulting study population was critically ill, with an expected mortality in excess of 50%. In- deed, our requirement of a cardiovascular SOFA score of 4 (indicating a norepinephrine dose of 0.1 mcg/kg/min) would, on average, equate to a minimum norepinephrine dose of 9.3 mcg/min, which based on our study drug titration protocol (Figure 1), would leave little room for titration. In order to allow for the possibility of a meaningful signal upon initiation of ATII, we preferentially considered patients with a substantially higher starting dose of norepinephrine (20 to 30 mcg/min, as evidenced in Figure 3). Moreover, we preferentially considered patients with an upward-trending norepinephrine requirement, sig- nifying refractoriness to therapy. Based on these facts, our results may not be generalizable to a less sick population. However, we foresee a use for ATII in a significant critically ill population, for whom multiple vasopressors are required. The initiation of an ATII infusion in patients receiving norepinephrine for septic shock resulted in a marked de- crease in norepinephrine doses. ATII may be effective as a novel pressor agent in the treatment of high-output shock. Initial dosing ranges are most likely between 2 and 10 ng/ kg/min. In our pilot study, the drug appears to be well- tolerated. Further randomized placebo-controlled trials to more fully elucidate the role of ATII as a vasopressor in the treatment of shock are ...
Context 2
... Exclusion criteria included patients with acute coronary syndrome, a known history of vasospasm or asthma, any patients currently experiencing bronchospasm, patients with active bleeding with an anticipated need for transfusion of >4 units of packed red blood cells, hemoglobin <7 g/dL, or any other condition that would contraindicate drawing serial blood samples. Upon enrollment in the study, patients were ran- domly assigned following simple randomization procedures (computerized random numbers) to receive either ATII acetate infusion (Clinalfa, Bachem AG, Hauptstrasse 144, 4416 Bubendorf, Switzerland) or a placebo infusion (hereafter referred to as the study drug and placebo, respectively). Randomization was accomplished by the Investigational Drug Services (IDS) at George Washington University Hospital. For the duration of the entire study, only the IDS was aware of each patient ’ s treatment assign- ment. Unblinding was done after all 20 patients were enrolled. All other clinical personnel, including the investigators, clinical support staff, the patients and their families were unaware of the treatment assign- ment for the duration of the study. Enrolled patients were randomized to receive the study drug infusion in normal saline calculated to run at a drip rate corresponding to an initial concentration of 20 ng/ kg/min, plus the standard-of-care treatment for high- output shock. The study drug was prepared in an opaque cellophane bag, the contents of which were unknown to the investigators, nurses or anyone else taking direct care of the patient. The study drug was adminis- tered for a total of 6 hours, with dose (and corresponding drip rate) adjustments made hourly. Study drug dose adjustments were determined per a pre-specified protocol, based on the concomitant requirements of standard- of-care therapy (in all cases, norepinephrine infusion plus vasopressin, epinephrine and/or phenylephrine infusions) needed to maintain a MAP at or above 65 mm Hg, which is the standard practice at our institution. The study drug titration protocol was designed to elucidate the dose of ATII that was required (in conjunction with a norepinephrine dose between 5 and 10 mcg/min) to achieve the aforementioned standard MAP goal of 65 mm Hg. The dose titration protocol is shown on Figure 1. The maximum allowable dose for the ATII titration was 40 ng/kg/min, and the minimum was 5 ng/kg/min. At the end of 6 hours, the study drug infusion was titrated off by halving it every 10 minutes until the study drug infusion dose was below 5 ng/kg/min, after which it was discontinued. The primary endpoint was the effect of the ATII infusion on the standing dose of norepinephrine that was required to maintain a MAP of 65 mmHg. The secondary endpoints included the effect of the ATII infusion on urine output, serum lactate, cardiac output, and 30-day mortality. This was a safety and dose-finding feasibility study. We analyzed a small cohort of patients, consistent with similar studies of this nature. We estimated that a population of 20 patients, 10 patients in each arm, would generate a basis for determining if there was sufficient signal for ATII to affect the dose of norepinephrine at the doses outlined herein. An independent data and safety monitor (DSM) was assigned and reviewed all adverse events. The DSM had the power to be unblinded and halt the study at any time during the conduct of the study. We assessed the distribution of demographic and clinical variables. Difference between proportions of patients with certain variables was assessed with the chi-square, Fisher exact, Student t -, or Mann – Whitney test as appropriate. The primary endpoint of the effect of the study drug infusion on the standing dose of norepinephrine was calculated using a general estimating equation analysis and is presented as the mean dose of norepinephrine (mcg/min) and study drug infusion (in ng/kg/ min) at hourly intervals. A generalized estimating equation was used to model the response to the study drug over time, with standard- of-care vasopressor hourly readings beginning at 1 hour prior to, through 8 hours after the initiation of the study drug, using the SAS Genmod procedure (version 9.3, Cary, NC, USA). Correlation structure was defined as auto-regressive to account for the likely higher correl- ation between time points that were closer together. In this model, the main effect of drug examines the mean response to each drug averaged across times. The main effect of time examines the mean response at each time point averaged across drugs, and the drug multiplied by time interaction examines whether the change over time differs between drugs. All values are reported as mean ± SD unless otherwise specified. All other statistical analysis was completed using SPSS 18, Chicago, IL, USA. The flow of patients into the study is reported in Figure 2: 20 patients underwent randomization and all 20 patients were enrolled in and completed the study (Figure 1). Baseline characteristics of the two groups are shown in Table 1. The mean age for all study subjects was 62.9 ± 15.8 years. Of the patients, 75% were male, 45% were Caucasian and 40% were African American. Baseline SOFA and acute physiology and chronic health evaluation II (APACHE II) scores were 15.9 ± 3.0 and 30.6 ± 8.9, respectively. Of the 20 patients 19 were receiving concomitant vasopressin at a dose of 0.02 to 0.08 u/min. Vasopressin doses were not adjusted during the study period. ATII resulted in a reduction in norepinephrine dosing in all patients (Figure 3). The mean hour-1 norepinephrine dose for the placebo cohort was 27.6 ± 29.3 mcg/min versus 7.4 ± 12.4 mcg/min for the ATII cohort ( P = 0.06). Hour 2 norepinephrine dosing for the placebo cohort was 28.6 ± 30.2 mcg/min versus 7.3 ± 11.9 mcg/min in the ATII cohort ( P = 0.06). Throughout the study period, the mean ATII dose was reduced from 20 ng/kg/min at hour 0 to 5 ng/kg/min at hour 6 before being titrated off by hour 7 (one hour post-infusion). Despite this down- titration of ATII, norepinephrine doses remained substantially lower in the ATII cohort than the placebo cohort, though the effect approached statistical significance only at hours 1 and 2. Upon cessation of the ATII infusion, mean norepinephrine rebounded concomitantly. Using a general estimating equation model with time defined as a continuous variable, in order to obtain a global test of interaction effect, the main effect of treatment (study drug versus placebo) was not significant ( P = 0.13), nor was the effect of time ( P =0.30), nor was the treatment multiplied by time interaction ( P = 0.76). When time was defined as a class variable with hour-1 defined as the reference group, in order to examine specific time points, the drug effect ( P = 0.14) and time effect ( P = 0.18 at time 0, P = 0.51 at time 1) both remained non-significant. The product of drug multiplied by time interaction showed a trend level of significance at 1 hour and 2 hours ( P = 0.06). Adverse events most commonly experienced by all patients were metabolic disorders with alkalosis occurring in four patients in the ATII group and no patients in the placebo group ( P = 0.09). The most common adverse event thought to be attributable to ATII was hypertension, which occurred in 20% of patients receiving ATII ( P = 0.58). In both of these patients, the study drug infusion was stopped, per protocol, in order to achieve MAP goals. Table 2 lists adverse events. Urine output, cardiac output, central venous pressure, and MAP are shown in Table 3. The 30-day mortality for the two groups was similar for the ATII cohort and the placebo cohort (50% versus 60%, P = 1.00). We report the findings of the first prospective randomized placebo-controlled trial of ATII in the treatment of high- output shock. Our efforts were intended as a proof-of- concept and dose-finding study, as well as an attempt to generate hypotheses in advance of larger future studies. To this end, we have shown that ATII can be an effective pressor agent at a dose range of 5 to 40 ng/kg/min. More specifically, we believe that a starting dose of 2 to 10 ng/ kg/min may be an appropriate starting dose in the treatment of high-output shock when used in conjunction with standard-of-care vasopressors. ATII has been used previously for the treatment of hypotension in a handful of cases. Newby et al . describe the successful treatment of a patient with an ACEi overdose and profound shock, using an ATII infusion [11]. Multiple case reports have shown potential utility for ATII in the treatment of septic shock with catecholamine infusions [12-16]. While all patients in the present study had a response to the ATII infusion, we observed significant heterogen- eity. Of the ten patients who received ATII, two had a modest response, while two were exquisitely sensitive to ATII, which was an unexpected finding. In the two highly sensitive patients, the norepinephrine infusion was titrated off per protocol, and the ATII dose was at its lowest allowable dose of 5 ng/kg/min and the patients remained hypertensive with MAP of >90 mm Hg, ...
Context 3
... with vasopressors, distributive shock is uni- formly fatal. The addition of a rescue vasopressor in this setting could be useful. Angiotensin II (ATII) is a naturally occurring hormone with endocrine, autocrine, paracrine, and intracrine hor- monal effects. It is a potent direct vasoconstrictor, con- stricting both arteries and veins and increasing blood pressure [6]. It has a half-life in circulation of approxi- mately 30 seconds, but while in tissue, its half-life may be as long as 15 to 30 minutes. Importantly, ATII increases secretion of antidiuretic hormone (ADH) and adrenocorticotropin hormone (ACTH), and may potentiate sympathetic effects by direct action on postganglionic sympathetic fibers. It also acts on the adrenal cortex, causing it to release aldosterone [6,7]. We hypothesized that ATII might serve a role as a useful vasopressor in the treatment of shock, but the appropriate dose of intravenous ATII to increase blood pressure is unknown. The dose of intravenous ATII previously described has varied across studies, but ranges from 0.4 ng/kg/min to as much as 40 ng/kg/min. The highest doses were reported in the cases of profound hypotension due to angiotensin-converting- enzyme inhibitor (ACEi) overdose [8,9]. We set out to de- termine the appropriate dose of ATII in the treatment of high output shock. The study was conducted at the George Washington University Hospital Intensive Care Unit, Washington DC, USA. The trial was registered on clinicatrials.gov (NCT01393782) and the study protocol was approved by the Food and Drug Administration (IND# BB-IND- 11592). The protocol was approved by the George Washington University Institutional Review Board. Writ- ten informed consent was obtained from each participat- ing patient or appropriate surrogate prior to enrollment. The investigators performed all experimental procedures and the study coordinators recorded the data. Patients were eligible for randomization if they were older than 21 years and were deemed to have high- output shock, which was defined as a cardiovascular sequential organ function assessment (SOFA) score of 4 as well as a cardiac index >2.4 L/min/BSA 1.73 m 2 [10]. Patients were also required to have an indwelling arterial line and urinary catheter as part of standard care and expected to be present for at least 12 hours during the study intervention. In addition, the treating team had to deem the subject adequately volume-resuscitated and clinically assessed not to be volume-responsive (that is, a fluid bolus would fail to increase cardiac index by 15%). Standard of care at our institution is to resuscitate with 20 to 30 cc/kg of crystalloid as initial resuscitation. Exclusion criteria included patients with acute coronary syndrome, a known history of vasospasm or asthma, any patients currently experiencing bronchospasm, patients with active bleeding with an anticipated need for transfusion of >4 units of packed red blood cells, hemoglobin <7 g/dL, or any other condition that would contraindicate drawing serial blood samples. Upon enrollment in the study, patients were ran- domly assigned following simple randomization procedures (computerized random numbers) to receive either ATII acetate infusion (Clinalfa, Bachem AG, Hauptstrasse 144, 4416 Bubendorf, Switzerland) or a placebo infusion (hereafter referred to as the study drug and placebo, respectively). Randomization was accomplished by the Investigational Drug Services (IDS) at George Washington University Hospital. For the duration of the entire study, only the IDS was aware of each patient ’ s treatment assign- ment. Unblinding was done after all 20 patients were enrolled. All other clinical personnel, including the investigators, clinical support staff, the patients and their families were unaware of the treatment assign- ment for the duration of the study. Enrolled patients were randomized to receive the study drug infusion in normal saline calculated to run at a drip rate corresponding to an initial concentration of 20 ng/ kg/min, plus the standard-of-care treatment for high- output shock. The study drug was prepared in an opaque cellophane bag, the contents of which were unknown to the investigators, nurses or anyone else taking direct care of the patient. The study drug was adminis- tered for a total of 6 hours, with dose (and corresponding drip rate) adjustments made hourly. Study drug dose adjustments were determined per a pre-specified protocol, based on the concomitant requirements of standard- of-care therapy (in all cases, norepinephrine infusion plus vasopressin, epinephrine and/or phenylephrine infusions) needed to maintain a MAP at or above 65 mm Hg, which is the standard practice at our institution. The study drug titration protocol was designed to elucidate the dose of ATII that was required (in conjunction with a norepinephrine dose between 5 and 10 mcg/min) to achieve the aforementioned standard MAP goal of 65 mm Hg. The dose titration protocol is shown on Figure 1. The maximum allowable dose for the ATII titration was 40 ng/kg/min, and the minimum was 5 ng/kg/min. At the end of 6 hours, the study drug infusion was titrated off by halving it every 10 minutes until the study drug infusion dose was below 5 ng/kg/min, after which it was discontinued. The primary endpoint was the effect of the ATII infusion on the standing dose of norepinephrine that was required to maintain a MAP of 65 mmHg. The secondary endpoints included the effect of the ATII infusion on urine output, serum lactate, cardiac output, and 30-day mortality. This was a safety and dose-finding feasibility study. We analyzed a small cohort of patients, consistent with similar studies of this nature. We estimated that a population of 20 patients, 10 patients in each arm, would generate a basis for determining if there was sufficient signal for ATII to affect the dose of norepinephrine at the doses outlined herein. An independent data and safety monitor (DSM) was assigned and reviewed all adverse events. The DSM had the power to be unblinded and halt the study at any time during the conduct of the study. We assessed the distribution of demographic and clinical variables. Difference between proportions of patients with certain variables was assessed with the chi-square, Fisher exact, Student t -, or Mann – Whitney test as appropriate. The primary endpoint of the effect of the study drug infusion on the standing dose of norepinephrine was calculated using a general estimating equation analysis and is presented as the mean dose of norepinephrine (mcg/min) and study drug infusion (in ng/kg/ min) at hourly intervals. A generalized estimating equation was used to model the response to the study drug over time, with standard- of-care vasopressor hourly readings beginning at 1 hour prior to, through 8 hours after the initiation of the study drug, using the SAS Genmod procedure (version 9.3, Cary, NC, USA). Correlation structure was defined as auto-regressive to account for the likely higher correl- ation between time points that were closer together. In this model, the main effect of drug examines the mean response to each drug averaged across times. The main effect of time examines the mean response at each time point averaged across drugs, and the drug multiplied by time interaction examines whether the change over time differs between drugs. All values are reported as mean ± SD unless otherwise specified. All other statistical analysis was completed using SPSS 18, Chicago, IL, USA. The flow of patients into the study is reported in Figure 2: 20 patients underwent randomization and all 20 patients were enrolled in and completed the study (Figure 1). Baseline characteristics of the two groups are shown in Table 1. The mean age for all study subjects was 62.9 ± 15.8 years. Of the patients, 75% were male, 45% were Caucasian and 40% were African American. Baseline SOFA and acute physiology and chronic health evaluation II (APACHE II) scores were 15.9 ± 3.0 and 30.6 ± 8.9, respectively. Of the 20 patients 19 were receiving concomitant vasopressin at a dose of 0.02 to 0.08 u/min. Vasopressin doses were not adjusted during the study period. ATII resulted in a reduction in norepinephrine dosing in all patients (Figure 3). The mean hour-1 norepinephrine dose for the placebo cohort was 27.6 ± 29.3 mcg/min versus 7.4 ± 12.4 mcg/min for the ATII cohort ( P = 0.06). Hour 2 norepinephrine dosing for the placebo cohort was 28.6 ± 30.2 mcg/min versus 7.3 ± 11.9 mcg/min in the ATII cohort ( P = 0.06). Throughout the study period, the mean ATII dose was reduced from 20 ng/kg/min at hour 0 to 5 ng/kg/min at hour 6 before being titrated off by hour 7 (one hour post-infusion). Despite this down- titration of ATII, norepinephrine doses remained substantially lower in the ATII cohort than the placebo cohort, though the effect approached statistical significance only at hours 1 and 2. Upon cessation of the ATII infusion, mean norepinephrine rebounded concomitantly. Using a general estimating equation model with time defined as a continuous variable, in order to obtain a global test of interaction effect, the main effect of treatment (study drug versus placebo) was not significant ( P = 0.13), nor was the effect of time ( P =0.30), nor was the treatment multiplied by time interaction ( P = 0.76). When time was defined as a class variable with hour-1 defined as the reference group, in order to examine specific time points, the drug effect ( P = 0.14) and time effect ( P = 0.18 at time 0, P = 0.51 at time 1) both remained non-significant. The product of drug multiplied by time interaction showed a trend level of significance at 1 hour and 2 hours ( P = 0.06). Adverse events most commonly experienced by all patients were metabolic disorders with alkalosis occurring in four patients in the ATII group and no patients in the placebo group ( P = 0.09). The most common adverse event thought to be attributable to ATII was hypertension, ...
Context 4
... study drug titration protocol was designed to eluci- date the dose of ATII that was required (in conjunction with a norepinephrine dose between 5 and 10 mcg/min) to achieve the aforementioned standard MAP goal of 65 mm Hg. The dose titration protocol is shown on Figure 1. The maximum allowable dose for the ATII titration was 40 ng/kg/min, and the minimum was 5 ng/kg/min. ...
Context 5
... flow of patients into the study is reported in Figure 2: 20 patients underwent randomization and all 20 patients were enrolled in and completed the study (Figure 1). Base- line characteristics of the two groups are shown in Table 1. ...
Context 6
... inclusion criteria for enrollment in the study were such that the resulting study population was critically ill, with an expected mortality in excess of 50%. In- deed, our requirement of a cardiovascular SOFA score of 4 (indicating a norepinephrine dose of 0.1 mcg/kg/min) would, on average, equate to a minimum norepinephrine dose of 9.3 mcg/min, which based on our study drug titra- tion protocol (Figure 1), would leave little room for titra- tion. In order to allow for the possibility of a meaningful signal upon initiation of ATII, we preferentially considered patients with a substantially higher starting dose of nor- epinephrine (20 to 30 mcg/min, as evidenced in Figure 3). ...

Similar publications

Article
Full-text available
Background Catecholamine agents are commonly used to support circulation; however, they may cause unexpected hypotension in a special situation. Here we describe the first unexpected case of hypotension in response to catecholamine agents. Case presentation A 29-year-old Japanese man with schizophrenia was transferred to our emergency department....

Citations

... In ATHOS-3, 30% of patients randomized to angiotensin II did not have a blood pressure response at hour-3 despite the use of large doses (up to 200 ng/kg/min) [4]. Conversely, a hyper-response phenomenon has also been described [74][75][76]. This diversity of response profile could mirror the diversity of RAAS alterations mechanisms described earlier. ...
Article
Full-text available
Recent years have seen a resurgence of interest for the renin–angiotensin–aldosterone system in critically ill patients. Emerging data suggest that this vital homeostatic system, which plays a crucial role in maintaining systemic and renal hemodynamics during stressful conditions, is altered in septic shock, ultimately leading to impaired angiotensin II—angiotensin II type 1 receptor signaling. Indeed, available evidence from both experimental models and human studies indicates that alterations in the renin–angiotensin–aldosterone system during septic shock can occur at three distinct levels: 1. Impaired generation of angiotensin II, possibly attributable to defects in angiotensin-converting enzyme activity; 2. Enhanced degradation of angiotensin II by peptidases; and/or 3. Unavailability of angiotensin II type 1 receptor due to internalization or reduced synthesis. These alterations can occur either independently or in combination, ultimately leading to an uncoupling between the renin–angiotensin–aldosterone system input and downstream angiotensin II type 1 receptor signaling. It remains unclear whether exogenous angiotensin II infusion can adequately address all these mechanisms, and additional interventions may be required. These observations open a new avenue of research and offer the potential for novel therapeutic strategies to improve patient prognosis. In the near future, a deeper understanding of renin–angiotensin–aldosterone system alterations in septic shock should help to decipher patients’ phenotypes and to implement targeted interventions.
... In 2009, experimental work in Gram-negative septic sheep introduced the concept that septic acute kidney injury (AKI) may be partly due to efferent arteriolar vasodilatation and reported a marked beneficial effect of ANGII infusion on renal function [2]. This "rediscovery" of ANGII led to pilot work in humans [3] and then to the commercial development of an ANGII preparation (Giapreza ® , La Jolla, San Diego, CA). This was followed by the Angiotensin II for the Treatment of High-Output Shock III (ATHOS-3) trial [4,5]. ...
... Angiotensin (1-9) can also generate angiotensin (1-7) via the action of peptidases and ACE. Angiotensin (1-7) is also a potential source of angiotensin IV and/or angiotensin (3)(4)(5)(6)(7). This complex and not well-understood system can act via action on the MAS oncogene receptor or the AT4 receptor or the AT2 receptor to counter regulate the effects of angiotensin II. ...
... Aberrant activation of the RAAS has been observed in severe sepsis, and the roles of Ang II in the regulation of septic hypotension are contradictory. Several clinical studies suggest that Ang II could be a rescue vasopressor that effectively enhances blood pressure in patients with vasodilatory shock and distributive shock [66][67][68]. However, other studies indicate that the use of Ang II is not able to restore sepsis-related hypotension, but is associated with organ damage and high mortality in septic patients [69]. ...
Article
Full-text available
Angiotensin converting enzyme 2 (ACE2) is a new identified member of the renin-angiotensin-aldosterone system (RAAS) that cleaves angiotensin II (Ang II) to Ang (1–7), which exerts anti-inflammatory and antioxidative activities via binding with Mas receptor (MasR). However, the functional role of ACE2 in sepsis-related hypotension remains unknown. Our results indicated that sepsis significantly reduced blood pressure and led to disruption between ACE-Ang II and ACE2-Ang (1–7) balance. ACE2 knock-in mice exhibited improved sepsis-induced mortality, hypotension and vascular dysfunction, while ACE2 knockout mice exhibited the opposite effects. Bone marrow transplantation and in vitro experiments confirmed that myeloid ACE2 exerted a protective role by suppressing oxidative stress, NO production and macrophage polarization via the Ang (1–7)-MasR–NF–κB and STAT1 pathways. Thus, ACE2 on myeloid cells could protect against sepsis-mediated hypotension and vascular dysfunction, and upregulating ACE2 may represent a promising therapeutic option for septic patients with hypotension.
... However, there are very few studies that have investigated the role of angiotensin II, not providing convincing evidence, therefore its application is currently limited. The results of studies indicate that angiotensin II effectively increases mean arterial pressure, is a safe vasopressor, shows a catecholamine-sparing effect, reduces norepinephrine doses, and thus their potential side effects (3). New research is needed to address questions about angiotensin II, including its optimal dosing and side effects. ...
Conference Paper
Full-text available
Sepsa predstavlja tesǩu organsku disfunkciju organa, uzrokovanu neadekvatnim odgovorom domacína na infekciju. Najcěsčǐ uzrok sepse je bakterijska infekcija. Ako se ne lecǐ na vreme, mozě dovesti do septicňog sǒka, multiorganske disfunkcije organa i na kraju do smrti (1). Lecěnje septicňog sǒka cěsto zahteva visoke doze kateholamina tokom duzěg vremenskog perioda. Prekomerna upotreba kateholamina povecáva smrtnost bolesnika u jedinicama intenzivnog lecěnja, mozě izazvati i brojne nezěljene efekte, ukljucǔjucí perifernu ishemiju, akutni infarkt miokarda, aritmije, povecánu potrosňju kiseonika i hiperglikemiju. Dodavanje drugog vazopresora sa drugacǐjim mehanizmom delovanja, obezbedilo bi odrzǎvanje odgovarajucég srednjeg arterijskog pritiska i moglo bi smanjiti nezěljene efekte kateholamina (2). Angiotenzin II je glavni proizvod sistema renin-angiotenzin-aldosteron, slozěnog hormonskog sistema koji ima znacǎjnu ulogu u regulaciji krvnog pritiska. On ima snazǎn vazokonstriktorski efekat, suzǎva arterije i vene, sťo dovodi do povecánja krvnog pritiska, a indirektno deluje preko aldosterona. Studije pokazuju da bi primena angiotenzina II mogla biti korisna u septicňom sǒku. Međutim, vrlo je malo studija koje su istrazǐvale ulogu angiotenzina II, ne dajucí ubedljive dokaze, zbog toga je njegova primena za sada ogranicěna. Rezutati studija ukazuju da je angiotenzin II e�ikasno povecáva srednji arterijski pritisak, da je bezbedan vazopresor, pokazuje efekat posťede kateholamina, smanjuje doze norepinefrina, a samim tim i njihove potencijalne nezěljene efekte (3). Neophodna su nova istrazǐvanja koja bi dala odgovore na brojna pitanja vezana za primenu angiotenzina II, posebno za njegove optimalne doze, kao i nezěljene efekte. Literatura 1. Martin GS. Sepsis, severe sepsis and septic shock: changes in incidence, pathogens and outcomes. Z. et al. Intravenous angiotensin II for the treatment of high-output shock (ATHOS trial): a pilot study. Crit Care. 2014 Oct 6;18(5):534.
... Two recent RCTs have shown a clinical benefit of angiotensin II in patients with vasodilatory shock [46,47]. The phase 3 Angiotensin II for the Treatment of High-Output Shock (ATHOS-3) trial examined the effect of angiotensin II on the mean arterial pressure (MAP) of patients with vasodilatory shock [47]. ...
... Two recent RCTs have shown a clinical benefit of angiotensin II in patients with vasodilatory shock [46,47]. The phase 3 Angiotensin II for the Treatment of High-Output Shock (ATHOS-3) trial examined the effect of angiotensin II on the mean arterial pressure (MAP) of patients with vasodilatory shock [47]. ATHOS-3 enrolled 321 patients with vasodilatory shock, who were then randomly assigned to either the angiotensin II group (n = 163) or the placebo group (n = 158); in these patients, angiotensin II treatment significantly increased MAP. ...
Article
Full-text available
Acute kidney injury (AKI) is an emerging public health problem worldwide and is associated with high morbidity and mortality. The high mortality rate can be attributed to the lack of pharmacological therapies to prevent and treat AKI. Renal replacement therapy (RRT) plays a pivotal role in the treatment of patients with severe AKI. However, the mortality rate of patients with AKI requiring RRT exceeds 50%. Although studies on RRT for AKI have begun to resolve some of the associated problems, many issues remain to be addressed. Notably, the optimal timing of the initiation of RRT for AKI is still being debated. Recently, new therapeutic strategies for AKI have been developed. Angiotensin II and recombinant alkaline phosphatase treatment are expected to improve the clinical outcomes of patients with distributive and vasodilatory shock. Moreover, mitochondrial-targeted agents have been developed for the treatment of patients with AKI. This review is focused on the optimal timing of RRT for AKI and the new pharmacological interventions and therapies for AKI.
... Angiotensin II causes vasoconstriction through stimulation of the renin-angiotensin system. Its synthetic form became recently available and was approved by the FDA in 2017 for septic or other distributive shock based on the result of the ATHOS-3 trial [102,103]. This trial included 344 patients randomized to angiotensin II or a placebo in addition to background vasopressors, with the primary endpoint being an increase in mean arterial pressure of at least 10 mmHg or at least 75 mmHg. ...
Article
Full-text available
Sepsis is a clinical syndrome encompassing physiologic and biological abnormalities caused by a dysregulated host response to infection. Sepsis progression into septic shock is associated with a dramatic increase in mortality, hence the importance of early identification and treatment. Over the last two decades, the definition of sepsis has evolved to improve early sepsis recognition and screening, standardize the terms used to describe sepsis and highlight its association with organ dysfunction and higher mortality. The early 2000s witnessed the birth of early goal-directed therapy (EGDT), which showed a dramatic reduction in mortality leading to its wide adoption, and the surviving sepsis campaign (SSC), which has been instrumental in developing and updating sepsis guidelines over the last 20 years. Outside of early fluid resuscitation and antibiotic therapy, sepsis management has transitioned to a less aggressive approach over the last few years, shying away from routine mixed venous oxygen saturation and central venous pressure monitoring and excessive fluids resuscitation, inotropes use, and red blood cell transfusions. Peripheral vasopressor use was deemed safe and is rising, and resuscitation with balanced crystalloids and a restrictive fluid strategy was explored. This review will address some of sepsis management’s most important yet controversial components and summarize the available evidence from the last two decades.
... Third, changes in the host genotype [31][32][33], varying organ-specific receptor expressions, and downregulation of distinct tissues [34] may result in a heterogeneous response to different types of vasopressors, which may be mitigated by early administration of multimodal vasopressors. Fourth, patients who respond to vasopressors have better outcomes than those who do not [12,17,35], highlighting the fact that treatment sensitivity should be addressed during vasopressor selection. Early administration of multimodal vasopressors may help assess a patient's sensitivity to vasopressors [12]. ...
Article
Full-text available
Background The association between the timing of administration of multiple vasopressors and patient outcomes has not been investigated. Methods This study used data from the MIMIC-IV database. Patients with sepsis who were administered two or more vasopressors were included. The principal exposure was the last norepinephrine dose when adding a second vasopressor. The cohort was divided into early (last norepinephrine dose < 0.25 μg/kg/min) and normal (last norepinephrine dose ≥ 0.25 μg/kg/min) groups. The primary outcome was 28-day mortality. Multivariable Cox analyses, propensity score matching, stabilized inverse probability of treatment weighting (sIPTW), and restricted cubic spline (RCS) curves were used. Results Overall, 1,437 patients who received multiple vasopressors were included. Patients in the early group had lower 28-day mortality (HR: 0.76; 95% CI: 0.65–0.89; p < 0.001) than those in the single group, with similar results in the propensity score-matched (HR: 0.80; 95% CI: 0.68–0.94; p = 0.006) and sIPTW (HR: 0.75; 95% CI: 0.63–0.88; p < 0.001) cohorts. RCS curves showed that the risk of 28-day mortality increased as the last norepinephrine dose increased. Conclusions The timing of secondary vasopressor administration is strongly associated with the outcomes of patients with sepsis.
... The main reason for the difference is the data source for the correction factor estimation. While Goradia et al. used a pilot single-center randomized trial published in 2012 in intensive care unit settings [42], we used a subsequent multicenter randomized trial published in 2017 [15]. Since the pilot trial was small in sample size and had baseline imbalances between angiotensin and placebo arms, we used only the larger trial to better estimate the equipotency of angiotensin II. ...
Article
Full-text available
Vasopressors and fluids are the cornerstones for the treatment of shock. The current international guidelines on shock recommend norepinephrine as the first-line vasopressor and vasopressin as the second-line vasopressor. In clinical practice, due to drug availability, local practice variations, special settings, and ongoing research, several alternative vasoconstrictors and adjuncts are used in the absence of precise equivalent doses. Norepinephrine equivalence (NEE) is frequently used in clinical trials to overcome this heterogeneity and describe vasopressor support in a standardized manner. NEE quantifies the total amount of vasopressors, considering the potency of each such agent, which typically includes catecholamines, derivatives, and vasopressin. Intensive care studies use NEE as an eligibility criterion and also an outcome measure. On the other hand, NEE has several pitfalls which clinicians should know, important the lack of conversion of novel vasopressors such as angiotensin II and also adjuncts such as methylene blue, including a lack of high-quality data to support the equation and validate its predictive performance in all types of critical care practice. This review describes the history of NEE and suggests an updated formula incorporating novel vasopressors and adjuncts.
... [5,90,91] Angiotensin II, a natural hormone, exerts marked vasoconstrictor effects by stimulating the renin-angiotensin-aldosterone system. [92] Recent trials find an adjunctive role of angiotensin II in managing distributive shock, but strong evidence for its routine clinical use is lacking. [5,[92][93][94] Inotropes Dobutamine, a synthetic catecholamine, is considered the inotropic agent of choice due to its predominant β1-adrenergic effects. ...
... [92] Recent trials find an adjunctive role of angiotensin II in managing distributive shock, but strong evidence for its routine clinical use is lacking. [5,[92][93][94] Inotropes Dobutamine, a synthetic catecholamine, is considered the inotropic agent of choice due to its predominant β1-adrenergic effects. However, its β2-adrenergic effects may worsen hypotension. ...
Article
Circulatory shock is a common condition that carries high morbidity and mortality. This review aims to update the critical steps in managing common types of shock in adult patients admitted to medical emergency and intensive care units. A literature review was performed by searching PubMed, EMBASE Ovid, and Cochrane Library, using the following search items: ("shock" OR "circulatory shock" OR "septic shock" OR "cardiogenic shock") AND ("management" OR "treatment" OR "resuscitation"). The review emphasizes prompt shock identification with tissue hypoperfusion, knowledge of the underlying pathophysiological mechanism, initial fluid resuscitation with balanced crystalloids, norepinephrine as the preferred vasopressor in septic and profound cardiogenic shock, and tailored intervention addressing specific etiologies. Point-of-care ultrasound may help evaluate an undifferentiated shock and determine fluid responsiveness. The approach to septic shock is improving; however, confirmatory studies are required for many existing (e.g., amount of initial fluids and steroids) and emerging (e.g., angiotensin II) therapies. Knowledge gaps and wide variations persist in managing cardiogenic shock that needs urgent addressing to improve outcomes.
... The Ang-2 for the Treatment of High-Output Shock (ATHOS) 3 trial demonstrated that Ang-2 could effectively increase MAP and blood pressure in vasodilatory shock patients who did not respond to high dose of conventional vasopressors. 7,8 Ang-2 is found to be able to normalize blood pressure in 15 patients out of 21 subjects in the previous study. 7,8 This systematic review aims to summarize the clinical outcomes of vasodilatory shock patients treated with Ang-2, such as mortality, length of stay, and MAP level (before and after). ...
... 7,8 Ang-2 is found to be able to normalize blood pressure in 15 patients out of 21 subjects in the previous study. 7,8 This systematic review aims to summarize the clinical outcomes of vasodilatory shock patients treated with Ang-2, such as mortality, length of stay, and MAP level (before and after). We also review the optimum Ang-2 dose concentration and decrease in vasopressor dose in Ang-2 treated patients. ...
Article
Full-text available
Background: Patients with severe vasodilation accompanied by refractory hypotension despite high doses of vasopressors were associated with a high mortality rate. The Ang-2 for the Treatment of High-Output Shock (ATHOS) 3 trial demonstrated that angiotensin 2 (Ang-2) could effectively increase MAP and blood pressure in vasodilatory shock patients. This systematic review aims to summarize the impact of Ang-2 for the treatment of vasodilatory shock on clinical outcomes, including length of stay, MAP level (before and after), and mortality also Ang-2 dose needed. Methods: A systematic search in PubMed, Sage, ScienceDirect, Scopus and Gray literature was conducted to obtain studies about the use of Ang-2 in vasodilatory shock patients. Results: In all of the studies that we obtained, there were different results regarding mortality in patients with vasodilatory shock with Ang-2. Mortality was significantly lower when Ang-2 was administered to patients with elevated renin. The initial dose of Ang-2 can be started at 10-20 ng/kg/min, but there is no agreement on the maximum dose. Ang-2 may be considered a third-line vasopressor if the targeted MAP has not been achieved after administration of norepinephrine >200 ng/kg/min for more than 6 hours. Although not statistically significant, the use of Ang-2 can reduce the length of stay in the ICU and in the hospital when compared to patients without Ang-2 therapy, in addition to reducing the dose of vasopressor. Conclusion: Overall, the use of Ang-2 has potential to be a regimen for patients with vasodilatory shock. Further study is needed to obtain more data.