Catecholamine-resistant Shock Research Articles

Metabolic acidosis as a predictor of outcome in critically ill children – A single-center prospective observational study

Background: Acid-base disorders are common in critically ill patients and contribute significantly to mortality and morbidity. Metabolic acidosis (MA) can be measured by pH, base deficit, serum bicarbonate, and anion gap. A study was conducted to determine the incidence and type of MA among children admitted to the pediatric intensive care unit (PICU) and to assess its roles as a predictor of outcomes in them. Subjects and Methods: Over 1 year, 100 children between 1 month and 12 years of age who presented to the PICU with an MA or developed it within 24 h of admission were prospectively enrolled. Clinicodemographic data, pediatric sequential organ failure assessment score at admission, clinical outcome, and serial measurements of anion gap, serum lactate, and bicarbonate level were recorded. Results: The incidence of MA was 60.2% with a majority (52%) being high anion gap metabolic acidosis (HAGMA). The predominant condition (39%) leading to MA was catecholamine-resistant shock with organ dysfunction. Peak lactate value and bicarbonate nadir had a significant positive correlation with the duration of mechanical ventilation and inotropic support, but only peak lactate value was significantly associated with mortality. A peak lactate value of 2.19 mmol/L yielded the highest sensitivity and specificity for predicting mortality. There was no association was found between peak anion gap and morbidity or mortality. Conclusions: MA was observed in 60% of children in PICU, with HAGMA being the most common type. Peak lactate value and bicarbonate nadir were correlated with high morbidity, but only peak lactate value was significantly associated with mortality.

Diastolic blood pressure impact on pediatric refractory septic shock outcomes

Septic shock is the progression of sepsis, defined as cardiovascular dysfunction during systemic infection, and it has a mortality rate of 40%-80%. Loss of vascular tone is an important pathophysiological feature of septic shock. Diastolic blood pressure (DBP) was reported to be associated with vascular tone. This study aimed to identify the associations of several hemodynamic indices, especially DBP, with outcome in pediatric septic shock to allow for timely interventions. Children with persistent catecholamine-resistant shock had a pulse index continuous cardiac output (PiCCO®) system implanted for invasive hemodynamic monitoring and were enrolled in the current study. Serial cardiac index, systemic vascular resistance index (SVRI), systolic blood pressure (SBP), mean arterial pressure (MAP), and DBP were recorded during the first 24h following PiCCO® initiation. All hemodynamic parameters associated with 28-day mortality were further analyzed using receiver operating characteristic curve analysis. Thirty-three children with persistent catecholamine-resistant shock were enrolled. The median age was 12 years and the youngest children were 5 years old. Univariate analysis noted that SVRI, SBP, MAP, and DBP were significantly higher, and shock index was significant lower, in survivors compared with non-survivors (p<0.05). In the multivariate analysis, only SVRI and DBP remained independent predictors of 28-day mortality. DBP had the best correlation with SVRI (r=0.718, n=219, p<0.001). The area under the receiver operating characteristic curves of SVRI and DBP for predicting 28-day mortality during the first 24h of persistent catecholamine-resistant shock were >0.75, indicating a good prediction for mortality. DBP correlated well with SVRI and it can serve as a predictor for mortality in pediatric septic shock. Furthermore, DBP was a superior discriminator of mortality when compared with SBP and MAP. A lower DBP was an independent hemodynamic factor associated with 28-day mortality.

Methylene Blue Use in Pediatrics

AbstractCatecholamine-resistant shock, also known as vasoplegia, is a challenging entity with a significant risk of mortality. We seek to provide further data on the safety and effectiveness of methylene blue (MB) for vasoplegic shock in the pediatric population. We conducted a retrospective observational study of pediatric patients admitted to the pediatric intensive care unit or pediatric cardiac intensive care unit at Mount Sinai Kravis Children's Hospital from 2011 to 2021 who received MB for refractory shock. A list of patients was obtained by performing a pharmaceutical query from 2011 to 2021 for “MB.” Chart review was performed to determine indication for use and to collect demographic and clinical data. There were 33 MB administrations: 18 administrations (16 unique patients) for vasoplegic shock, 11 for surgical dye, and 4 for methemoglobinemia. The median age was 5 years (interquartile range [IQR]: 0.08, 13). Ten patients required MB following congenital cardiac repair (62.5%); one administration for myocarditis, septic shock, postcardiac arrest, high output chylothorax, scoliosis repair, and one multisystem inflammatory syndrome in children. No patients experienced hemolytic anemia or serotonin syndrome following administration. The median dose of MB was 1 mg/kg. Vasoactive-inotrope score (VIS) improved in 4 out of 18 administrations at 1 hour. Mean arterial pressure (MAP) improved in 10 out of 18 administrations at 1 hour. Systolic blood pressure (SBP) improved in 8 out of 18 administrations at 1 hour. VIS, MAP, and SBP improved in 8 out of 18 administrations at 6 hours. MB may be safely considered as rescue therapy in catecholamine-resistant shock in pediatrics.

LINC-04. Optic pathway gliomas in children: an 18-year experience in a middle-income country

Abstract BACKGROUND: Optic pathway gliomas (OPGs) have favorable survival outcomes, but can have significant morbidity, from the tumor or from its treatment. This retrospective study sought to describe the clinical presentation and outcomes of children with OPGs at a tertiary center in a middle-income country. METHODS: Patients younger than 18 years diagnosed with OPGs between 2002-2020 at the Hospital Civil de Guadalajara in Mexico, were included. Survival analyses and logistic regression were used to determine risk factors for progression. RESULTS: Thirty patients were identified with a median age of six years. Common clinical characteristics at presentation included: visual accuracy impairment (40%), headache (23.3%), nystagmus (20%), endocrine disturbances (16.6%), and diencephalic syndrome (13%). Neurofibromatosis-1 was present in 23.3% of the patients. Eight patients underwent resection at diagnosis, 7 of them had secondary complications. One died during surgery due to catecholamine-resistant shock, and the other developed neuro-infection and died due to septic shock after surgery. Five children developed neurological or endocrine sequelae. Fifteen total patients received chemotherapy as their first line treatment. The 5-year progression-free survival was 77.9±10% and overall survival was 89.5±5%. Patients who received chemotherapy or targeted therapy as the first line of treatment had higher PFS compared to those who received other therapies (p=0.03). The patients who received surgery as first-line treatment had a 3.1 times greater risk of achieving a Lansky/Karnofsky score of fewer than 90 points 6 months after diagnosis (p=0.006). Ten patients had pre- and post-treatment ophthalmologic assessment, either visual acuity or visual evoqued potentials. Five had no changes and 5 showed improvement after treatment. CONCLUSIONS: These results show inferior outcomes compared to high-income countries, influenced importantly due to morbidity after surgical resection. These data can be used to prospectively optimize treatment at our institute and other middle-income countries through a multidisciplinary neuro-oncology team.

The Use of Levosimendan in the Treatment of Neurogenic Stress Cardiomyopathy in a Patient with Nontraumatic Subarachnoid Hemorrhage (Case Report)

We present a case of cardiogenic shock due to neurogenic stress cardiomyopathy (NSC) in a patient with nontraumatic subarachnoid hemorrhage caused by a ruptured aneurysm of the right pericallosal artery. Due to the catecholamine-resistant shock, levosimendan was administered under advanced hemodynamic control, including transpulmonary thermodilution and echocardiography. This resulted in an improved cardiac contractility and reduced demand for catecholamines. Full stabilization of hemodynamic parameters was achieved by day 5. In the discussion section we reviewed available published case reports of using levosimendan in stress cardiomyopathy treatment.

A fatal toxic shock-like syndrome post COVID-19 infection in a child

BackgroundChildren affected by Coronavirus disease 2019 (COVID-19) showed various manifestations. Some of them were severe cases presenting with multi-system inflammatory syndrome (MIS-C) causing multiple organ dysfunction.Case presentationWe report the case of a 12-year-old girl with recent COVID-19 infection who presented with persistent fever, abdominal pain and other symptoms that meet the definition of MIS-C. She had lymphopenia and a high level of inflammatory markers. She was admitted to pediatric intensive care unit since she rapidly developed refractory catecholamine-resistant shock with multiple organ failure. Echocardiography showed a small pericardial effusion with a normal ejection fraction (Ejection Fraction = 60%) and no valvular or coronary lesions. The child showed no signs of improvement even after receiving intravenous immunoglobulin, fresh frozen plasma, high doses of Vasopressors and corticosteroid. His outcome was fatal.ConclusionPediatric patients affected by the new COVID-19 related syndrome may show severe life-threatening conditions similar to Kawasaki disease shock syndrome. Hypotension in these patients results from heart failure and the decreased cardiac output. We report a new severe clinical feature of SARS-CoV-2 infection in children in whom hypotension was the result of refractory vasoplegia.

EFFICACY OF NOVEL SYNTHETIC ANGIOTENSIN II IN SEPTIC SHOCK

SESSION TITLE: Critical Care Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: October 18-21, 2020 PURPOSE: Septic shock is a form of distributive shock characterized by decreased organ perfusion secondary to a dysregulated host response to infection. Septic shock has been associated with life-threatening multiple organ dysfunction and staggering mortality, with some studies estimating mortality greater than 50%. One of the cornerstones of improving outcomes has been maintaining adequate mean arterial pressure with vasopressors. Preliminary trials have shown that synthetic angiotensin II, a novel category of vasopressors which acts directly on the renin-angiotensin-aldosterone system, has significant vasopressor effect with no significant difference in serious adverse effects. Our study examined the effects of synthetic angiotensin II as a third-line agent in septic shock, comparing the change in MAP three hours after initiation, lactate clearance three hours after initiation, length of ICU stay, and cost. METHODS: We conducted a retrospective cohort study examining patients with septic shock on two vasopressors, with catecholamine-resistant shock (total catecholamine dose requirement >0.2 mcg/kg/min), requiring the initiation of a third agent. We compared patients who received synthetic angiotensin II versus a control group of any other appropriate third-line vasopressor. The protocol was approved by the IRB at Orange Regional Medical Center and data was obtained from the charts of ICU patients at the same hospital. RESULTS: There was a statistically significant increase in MAP at three hours in the angiotensin II group compared to the control group (16.3 mmHg vs. 4.3 mmHg; p = 0.0304). Overall, lactic acid clearance at 3 hours in the angiotensin II group was better than in the control group (13.39% vs. -57.2%), but was not statistically significant (p = 0.1338). Length of ICU stay did not statistically differ between the groups (433.6 hours vs 402.9 hours; p = 0.8370). Cost was significantly higher in the angiotensin II group versus the control group ($5717.84 vs. $1267.21; p < 0.0001). CONCLUSIONS: In our study of patients with catecholamine-resistant septic shock, initiation of synthetic angiotensin II as a third-line agent showed a significant improvement in MAP at 3 hours compared to other traditional third-line agents, without improvement in lactate clearance or ICU length of stay and at significantly higher cost. While showing promise as a potent vasopressor, given that angiotensin II has not yet demonstrated significant reductions in length of ICU stay, duration of mechanical ventilation, or mortality, the cost effectiveness of its use should also be taken into consideration. CLINICAL IMPLICATIONS: In the setting of catecholamine-resistant septic shock, our data shows that synthetic angiotensin II is associated with significant improvement in MAP at three hours compared to traditional third-line vasopressors and may play an important role in patients with catecholamine-resistant shock. DISCLOSURES: No relevant relationships by Maria Chaudhry, source=Web Response No relevant relationships by Murali Krishna, source=Web Response No relevant relationships by Karthika Linga, source=Web Response No relevant relationships by Isaac Pak, source=Web Response No relevant relationships by Lauren Stuczynski, source=Web Response

Effect of Vasopressin on Systemic and Pulmonary Hemodynamics in Neonates.

Despite its increasing use in neonates, the literature on the use of vasopressin (VP) in neonates is limited. The aim of this study is to evaluate the systemic and pulmonary effects of VP in neonates and to assess its safety among them. This retrospective study enrolled all neonates in two level III neonatal intensive care units in Winnipeg, Manitoba, who had received VP therapy between 2011 and 2016. Infants with congenital malformations/chromosomal disorders were excluded. The changes in cardiovascular and pulmonary parameters were collected from patient charts. The primary outcome was the mean blood pressure (MBP) post-VP initiation. Secondary outcomes included systolic blood pressure (SBP) and diastolic blood pressure (DBP), vasoactive inotropic score (VIS), pH, urine output, lactate, base deficit (BD), mean airway pressure (MAP), and oxygen requirement. A total of 33 episodes from 26 neonates were analyzed. The postnatal age at VP initiation was 14 days (interquartile range [IQR]: 4-25), and the median starting dose was 0.3 mU/kg/min (IQR: 0.2-0.5). MBP improved significantly after VP initiation from 28 to 39 mm Hg 24 hours after VP initiation (p < 0.001). Similar changes are observed with SBP and DBP. VIS declined from 15 to 6 at 24 hours, while pH, lactate, BD, and oxygen requirement improved significantly. While urine output marginally improved, there were no changes to MAP 24 hours post-VP initiation. Hyponatremia was observed in 21 episodes (64%) and severe hyponatremia in 7 episodes (33%). VP appears to be a promising rescue therapy in catecholamine resistant shock or refractory pulmonary hypertension in neonates.

Diabetes Insipidus After Discontinuation of Vasopressin Infusion for Treatment of Shock.

Vasopressin has achieved common usage for the treatment of catecholamine-requiring and catecholamine-resistant shock. Diabetes insipidus is a syndrome characterized by excretion of abnormally large volumes of dilute urine. To date, very few reports of diabetes insipidus after discontinuation of vasopressin infusion have been published; the majority of previous reports describe neurosurgical patients. The purpose of the present study was to investigate the occurrence rate of diabetes insipidus after discontinuation of vasopressin infusion among patients treated with vasopressin infusion for shock. Retrospective analysis of electronic health records of patients receiving continuous vasopressin infusion for the treatment of shock within a 5-year period (2012-2016). Medical, surgical, and cardiothoracic ICUs within one academic medical center. One-thousand eight-hundred ninety-six patients received vasopressin infusion for the treatment of shock. None. The occurrence rate of diabetes insipidus after discontinuation of vasopressin infusion was 1.53% among all patients. Sixteen of 29 patients with diabetes insipidus after discontinuation of vasopressin infusion had undergone cardiothoracic intervention, such as coronary artery bypass graft and valve replacement surgery, extracorporeal membrane oxygenation, and placement of ventricular assist devices. No neurosurgical patients were identified in our cohort. In a control group of patients receiving norepinephrine but not vasopressin infusion for treatment of shock, criteria for diabetes insipidus were observed in two of 1,320 subjects (0.15%). Despite a paucity of published reports, diabetes insipidus after discontinuation of vasopressin infusion appears not to be a rare phenomenon, and is likely to be encountered by intensivists who regularly employ vasopressin for the treatment of vasoplegic shock. Previous reports consisted predominantly of neurosurgical patients. Our findings demonstrate the occurrence of diabetes insipidus after discontinuation of vasopressin infusion among patients with septic shock as well as vasoplegic shock after cardiothoracic intervention. The mechanism of diabetes insipidus after discontinuation of vasopressin infusion remains to be elucidated but may involve transient downregulation of V2 receptors induced by exposure to supraphysiological doses of vasopressin.

Pediatric sepsis update

Pediatric sepsis comprises a spectrum of disorders that result from infection by bacteria, viruses, fungi, or parasites. Sepsis ranges from bacteremia, with early signs of circulatory compromise to complete collapse with multiple organ dysfunction and death. Early recognition improves outcomes for infants and children. Over the past two decades, sepsis has been defined and redefined with modifications for the pediatric population. The most recent iteration, complementing the NICE guideline (NG51) “Sepsis: Recognition, diagnosis and early management”, was published in 2017.1 Pediatric severe sepsis usually is community-acquired (57%) with the respiratory tract as the primary site of infection. Mortality rates associated with sepsis and septic shock in patients admitted to the pediatric intensive care unit are 5.6% and 17.0%, respectively.2 The SIRS adult criteria have been modified to produce pediatric-specific definitions. Per the 2017 Sepsis-3 guidelines, sepsis in adults is no longer based on the SIRS criteria, rather it is defined as an infection with at least one organ dysfunction. Although it may change in the future, the definition for the pediatric population remains based on the SIRS criteria due to weak evidence.3,4 Although not included in the definition of sepsis, hyperglycemia, altered mental status, and high lactate, are highly suggestive of sepsis and should be considered when evaluating a patient.Risk factors for pediatric sepsis include less than one month of age, serious injury, chronic medical problems, immunosuppression, indwelling devices, and urinary tract abnormalities. Sepsis should be in the differential diagnosis in children with persistently abnormal vital signs such as tachycardia that is often missed and attributed to other causes. Hypotension is a late finding in children; the diagnosis of shock cannot be based solely on this finding. Unlike adults, previously healthy children can compensate extremely well during hypoperfusion states and do so for relatively long periods resulting in sudden decompensation.2 Timely response to sepsis is vital to survival. Vascular access needs to be obtained, fluids administered (minimum of 60 ml/kg), broad spectrum antibiotic coverage and initiation of inotropic support in fluid refractory shock need to occur within the first hour. Hydrocortisone should be considered with catecholamine-resistant shock and if at risk for absolute adrenal insufficiency. Laboratory diagnostics such as white blood cell count (WBC) and erythrocyte sedimentation rate (ESR) are often nonspecific. More novel tests such as lactate and procacitonin are more specific clinical adjuncts that will support diagnosis, monitor, and trend a child's progress.1,5 Key recommendations of the 2017 guidelines highlighted the importance of bundles: “recognition bundle” with trigger tools for rapid identification; “resuscitation and stabilization bundle” to increase adherence with best practice principles; and a “performance bundle” to identify gaps and barriers in the system.1 Not every child with fever will have a serious infection leading to sepsis. Delays in recognition and management will worsen the prognosis significantly; early recognition is crucial. Any child with a suspected infection, persistently abnormal vital signs, or a concerning exam after antipyretics and intravenous fluids should be investigated and treated for sepsis. Rapidly changing standard of care makes sepsis a critical diagnosis for clinicians.

Postoperative catecholamine resistance following fetal methamphetamine exposure

Methamphetamine and its related compounds are among the most widely abused recreational drugs worldwide. While a myriad of clinical complications of methamphetamine use have been described, there is a paucity of literature regarding the effects of maternal abuse during pregnancy on neonatal hearts. In this report, we describe a neonate who underwent Norwood-type palliation and subsequently developed catecholamine-resistant cardiogenic shock, likely related to methamphetamine exposure, which recovered after a period of venoarterial extracorporeal membrane oxygenation support.

Clinical profile and outcome of dengue in children admitted in pediatric intensive care unit in a tertiary center in South India

Background: As dengue being a tropical infection presenting with varying degrees of severity of illness in Indian children, present study is aimed at studying the clinical profile, outcome, predictors for mortality of moderate and severe dengue cases admitted to PICU in a tertiary care center in South India. Methods: It is a retrospective observational study. All patients admitted in PICU from April 2016 to March 2017 were included in the study. Patients were classified based on National Vector Borne Disease Control Program (NVBDP). Clinical characteristics, laboratory parameters, complications, outcome and predictors for mortality were studied. Results: All 58 seropositive dengue cases admitted were included. Most common presenting symptoms were fever in 58 (100%), vomiting in 33 (56.8%) and abdomen pain in 19 (32.7%). Among severe dengue, expanded dengue syndrome was present in 10 (30%), expanded dengue syndrome with shock was present in 10 (30%), significant hemorrhage with shock in 2 (6%), hemorrhage without shock in 1(3%) and combination of expanded dengue syndrome with hemorrhage and shock in 10 (30%).Pleural effusion was present in 38 (65.5%) and ascites in 18(31%) children. Among severe dengue,12(36.3%) received invasive mechanical ventilation,8(24%) received inotropes,19(57.5%) received steroids and 7 (21%) had abdomen compartment syndrome requiring drainage of ascites. Conclusion: Significantly more number of children who died received ventilator support and inotropes. Commonest cause of death is catecholamine resistant shock. There is no major adverse effect of steroids when used in severe dengue.

Role of ScvO2 in the Management of Fluid Refractory and Cathecholamine Resistant Shock among Children: A Hospital Based Randomized Controlled Trial

ackground: The highest mortality rates are observed in children under five years in developing countries. Shock is the result of various etiologies and the leading causes of shock in children younger than 5 years of age. More specifically, the outcome benefit of further optimizing metabolic parameters, namely ScvO2, directed therapy remains unknown. Even though current ACCM/PALS guidelines represent best practice, prospective randomized trials are lacking to confirm all components of these recommendations. Hence the present study was undertaken to assess the role of ScvO2 in management of fluid refractory. Methods: The study design was one year randomized controlled trial. Institutional Ethical Clearance was obtained for the study prior beginning of the study. Children fulfilling the selection criteria were selected After obtained written informed consent, demographic data was recorded and history was taken. Clinical examination was done for all patients and findings were recorded on predesigned and pretested proforma. Result: 31.37% children in group A and 27.45% in group B presented with fever. Majority of the children were hypotensives. 66.67% of patients in both the groups had ephedrine. Outcome among children with group B was significantly better (94.12%) compared to group A (80.39%) supporting the current ACCM/PALS guidelines. Conclusion: It may be concluded that, ScvO2 in management of fluid refractory and catecholamine resistant shock has reduced the mortality but did not influence the hospital stay.

A brief review of the use of vasopressin in critically ill children

Robust clinical evidence for the use of vasopressin in children is scant. Low dose vasopressin infusions may be tried in catecholamine resistant shock or refractory cardiac arrest. It significantly improves hemodynamic indices without necessarily translating into clinical benefit. There appears to be a trend to greater tissue ischemia with its use. Evidence to date has not demonstrated clear efficacy for vasopressin’s routine use in management of pediatric shock. Further high-quality research is essential before it can be recommended as a routine standard of care.

Angiotensin II: a new approach for refractory shock management?

Patients with distributive shock still have a high mortality rate and remain an important issue for intensivists. Management of catecholamine-resistant shock in these patients poses a challenging problem. Despite significant advances in the knowledge of its pathophysiology, all innovative therapeutic approaches and interventions have failed to improve outcome. In the previous issue of Critical Care, Chawla and colleagues explored the impact of angiotensin II administration in patients with persistent hypotension despite adapted hemodynamic resuscitation. The authors demonstrate that, in case of distributive shock, angiotensin II is an effective vasopressor therapy. Its impact on outcome and adverse effects still needs to be further explored.

Stress Response in Critical Illness

Sepsis brings about neuroendocrine dysfunction in children that differs significantly from that of adults and can thus be difficult to interpret and manage. Aggressive treatment of sepsis with appropriate and judicious use of antibiotics remains a top priority. Strict glycemic control in children has been associated with significant risk of hypoglycemia, which may independently contribute to morbidity and mortality. Timely initiation of hydrocortisone in persistently hypotensive children with fluid-refractory, catecholamine-resistant shock is controversial, but its use in children with suspected or proven adrenal insufficiency is suggested. Fluid and electrolyte abnormalities must be corrected. Treatment of thyroid dysfunction has been shown to be beneficial in certain specific populations but cannot be extrapolated to all septic patients with the current available data.

水中毒患者のカテコラミン不応性ショックにバゾプレッシンが著効した一症例

水中毒患者のカテコラミン不応性ショックにバゾプレッシンが著効した一症例

Recent Advances in Perioperative Anesthetic Management Update on the Role of Vasopressin and its Effects on Outcomes

The vasoconstrictive and antidiuretic physiologic properties of vasopressin (antidiuretic hormone) have long been known. Until recently however, vasopressin was mostly used for diabetes insipidus and noctournal enuresis. This review summarizes the growing body of evidence regarding the perioperative use of vasopressin and its analogues in the management of certain forms of cardiovascular collapse. Physiologically, vasopressin is involved in regulating osmotic, volemic, and cardiovascular homeostasis. It acts via several specific vasopressin receptors that are variably distributed in the heart, kidneys and vasculature etc. Under normal conditions, its antidiuretic effect predominates and vasopressin only induces vasoconstriction at high concentrations. Regarding catecholamine-resistant vasodilatory shock, current evidence suggests that with adequate volume resuscitation, exogenous vasopressin in low "physiologic" doses (0.01-0.04 units/min) safely supports mean arterial pressure without adversely affecting myocardial function and splanchnic circulation. One possible explanation is that metabolic acidosis impairs the function of alpha-adrenergic (but not vasopressin) receptors, thus diminishing the response to catecholamines. Although there is yet no clear cut mortality benefit, vasopressin is now recommended as a second-line agent in septic shock for its catecholamine-sparing effect and as an alternative to epinephrine in cardiopulmonary resuscitation. It has also demonstrated efficacy in ameliorating vasoplegia after cardiopulmonary bypass as well as perioperative hypotension in patients on renin-angiotensin system antagionists preoperatively. In summary, accumulating clinical experience and formal studies indicate that vasopressin has a role in restoring vascular tone in refractory vasodilatory shock states with minimal adverse effects provided that euvolemia is assured.

Vasopressin-Mediated Enhancement of Adrenergic Vasoconstriction Involves Both the Tyrosine Kinase and the Protein Kinase C Pathways

Vasopressin is frequently used to treat catecholamine-resistant vasodilatory shock. It enhances the vasoconstrictor effects of catecholamines at concentrations of vasopressin that have none or only minimal intrinsic pressor effects. However, the vascular mechanisms underlying this combined pharmacological approach have not been fully elucidated. We used isometric tension measurements in vascular rings to investigate potential cellular mechanisms. Vascular rings (0.2 mm diameter) were harvested from the superior mesenteric artery of Wistar rats (2 to 4 months of age). Dose-response relationships were derived for vasopressin (VP) and norepinephrine (NE), in the absence and presence of a subpressor dose of VP (10(-9) M). The contribution of tyrosine kinase (TK), the TK pathway proteins SRC and PYK2, as well as protein kinase C (PKC) were determined by measuring the modulating influence of specific inhibitors on the pressor response to NE (10(-5) M) alone and the augmented pressor response to VP (10(-9) M). VP (10(-9) M) had only minimal pressor effect alone (10% of maximal response), but significantly increased the E(max) response to NE (587.8 ± 40.7 vs 331.2 ± 10.4 mg). TK inhibition completely abolished the pressor response to NE (100% vs 1.0% 0.5%) and the augmented VP response alone (100% vs 2.0% ± 1.01%). Both responses were significantly, but equally, decreased by SRC inhibition (63% ± 4.0% and 69% 1.0%). In contrast, inhibition of the TK molecule PYK2 with salicylate had differential inhibitory effects on the vasoconstrictor responses. Salicylate caused a greater inhibition of VP-induced augmented NE response in comparison with NE alone (62.1% ± 7% and 15% ± 2%). Inhibition of either the µ or γ PKC isoform significantly decreased both responses, but the magnitude of the inhibition was significantly different for each isoform. Inhibition of the γ PKC isoform significantly decreased the vasoconstriction responses to both NE and VP plus NE (82.9 ± 3.9 vs 32.8 ± 3.8). Inhibition of the µ PKC isoform significantly decreased both responses and completely abolished the VP-augmented response to NE. These data are consistent with a central role for TK in mediating both the NE response and the VP-augmented response. Moreover, PYK2 and the µ and γ isoforms of PKC seem to play a preferential role in mediating the augmented VP response. The apparent divergent roles of these pathways in mediating NE- versus VP-augmented pressor responses could potentially lead to new targeted therapies in catecholamine-resistant shock.

The response to methylene blue in patients with severe hypotension during liver transplantation

Methylene blue is a useful therapy for catecholamine-resistant vasoplegic shock. Three cases of methylene blue administration for the treatment of catecholamine-resistant hypotension during orthotopic liver transplantation are presented.