Treatment of intraoperative hypotension with cafedrine/theodrenaline versus ephedrine

Background Sympathomimetic drugs are a therapeutic cornerstone for the management of hypotensive states like intraoperative hypotension (IOH). While cafedrine/theodrenaline (C/T) is widely used in Germany to restore blood pressure in patients with IOH, more research is required to compare its effectiveness with alternatives such as ephedrine (E) that are more commonly available internationally. Methods HYPOTENS (NCT02893241, DRKS00010740) was a prospective, national, multicenter, open-label, two-armed, non-interventional study that compared C/T with E for treatment of IOH. We describe a prospectively defined cohort of patients ≥50 years old with comorbidities undergoing general anesthesia induced with propofol and fentanyl. Primary objectives were to examine treatment precision, rapidity of onset and the ability to restore blood pressure without relevant increases in heart rate. Secondary endpoints were treatment satisfaction and the number of required additional boluses or other accompanying measures. Results A total of 1496 patients were included in the per protocol analysis. Overall, effective stabilization of blood pressure was achieved with both C/T and E. Post-hoc analysis showed that blood pressure increase from baseline was more pronounced with C/T. Fewer additional boluses or other accompanying measures were required in the C/T arm. The incidence of tachycardia was comparable between groups. Post-hoc analysis showed that E produced dose-dependent elevated heart rate values. By contrast, heart rate remained stable in patients treated with C/T. Physicians reported a higher level of treatment satisfaction with C/T, with a higher proportion of anesthetists rating treatment precision and rapidity of onset as good or very good when compared with E. Conclusion Neither drug was superior in restoring blood pressure levels; however, post-hoc analyses suggested that treatment is more goal-orientated and easier to control with C/T. Heart rate was shown to be more stable with C/T and fewer additional interventions were required to restore blood pressure, which could have contributed to the increased treatment satisfaction reported by anesthetists using C/T.

Norepinephrine pressor infusion withdrawal in a National Health Service hospice

Norepinephrine (NE) is a peripheral vasoconstrictor used as an emergency measure to restore blood pressure secondary to acute hypotension. NE must be administered centrally as a continuous infusion and requires intensive monitoring. Consequently, its use is restricted to critical care environments. We discuss the withdrawal of NE in a hospice for a patient with advanced malignancy and profound hypotension from sepsis. The patient was admitted to intensive care but chose to stop active treatment and insisted on being discharged. Due to concerns about withdrawing NE in the community, he was transferred to a local hospice. We describe various challenges, including the administration and monitoring of NE outside of intensive care, the withdrawal process and concerns that profound hypotension might compromise subcutaneous medications absorption.

Vasopressin in Hemorrhagic Shock: A Systematic Review and Meta-Analysis of Randomized Animal Trials

Objective.The latest European guidelines for the management of hemorrhagic shock suggest the use of vasopressors (norepinephrine) in order to restore an adequate mean arterial pressure when fluid resuscitation therapy fails to restore blood pressure. The administration of arginine vasopressin (AVP), or its analogue terlipressin, has been proposed as an alternative treatment in the early stages of hypovolemic shock.Design.A meta-analysis of randomized controlled animal trials.Participants.A total of 433 animals from 15 studies were included.Interventions.The ability of AVP and terlipressin to reduce mortality when compared with fluid resuscitation therapy, other vasopressors (norepinephrine or epinephrine), or placebo was investigated.Measurements and Main Results.Pooled estimates showed that AVP and terlipressin consistently and significantly improve survival in hemorrhagic shock (mortality: 26/174 (15%) in the AVP group versus 164/259 (63%) in the control arms;OR=0.09; 95% CI 0.05 to 0.15;Pfor effect < 0.001;Pfor heterogeneity = 0.30;I2=14%).Conclusions.Results suggest that AVP and terlipressin improve survival in the early phases of animal models of hemorrhagic shock. Vasopressin seems to be more effective than all other treatments, including other vasopressor drugs. These results need to be confirmed by human clinical trials.

Combined administration of hyperbaric oxygen and hydroxocobalamin improves cerebral metabolism after acute cyanide poisoning in rats

Hyperbaric oxygen therapy (HBOT) or intravenous hydroxocobalamin (OHCob) both abolish cyanide (CN)-induced surges in interstitial brain lactate and glucose concentrations. HBOT has been shown to induce a delayed increase in whole blood CN concentrations, whereas OHCob may act as an intravascular CN scavenger. Additionally, HBOT may prevent respiratory distress and restore blood pressure during CN intoxication, an effect not seen with OHCob administration. In this report, we evaluated the combined effects of HBOT and OHCob on interstitial lactate, glucose, and glycerol concentrations as well as lactate-to-pyruvate ratio in rat brain by means of microdialysis during acute CN poisoning. Anesthetized rats were allocated to three groups: 1) vehicle (1.2 ml isotonic NaCl intra-arterially); 2) potassium CN (5.4 mg/kg intra-arterially); 3) potassium CN, OHCob (100 mg/kg intra-arterially) and subsequent HBOT (284 kPa in 90 min). OHCob and HBOT significantly attenuated the acute surges in interstitial cerebral lactate, glucose, and glycerol concentrations compared with the intoxicated rats given no treatment. Furthermore, the combined treatment resulted in consistent low lactate, glucose, and glycerol concentrations, as well as in low lactate-to-pyruvate ratios compared with CN intoxicated controls. In rats receiving OHCob and HBOT, respiration improved and cyanosis disappeared, with subsequent stabilization of mean arterial blood pressure. The present findings indicate that a combined administration of OHCob and HBOT has a beneficial and persistent effect on the cerebral metabolism during CN intoxication.

Effects of Vasopressin in Septic Shock

Septic shock continues to be one of the leading causes of death in the intensive care unit today. The confluence of many factors contributes to the deterioration of patients’ condition in septic shock. Increased levels of nitric oxide, in part, mediate the cardiovascular effects of septic shock. Nitric oxide is major mediator of vasodilation and hypotension as well as myocardial depression. It also contributes to decreased production and release of endogenous vasopressin. Vasopressin effects are actualized by stimulation of V1, V2, and V3 receptors located in various parts of the body. The response is dose dependent. Endogenous vasopressin and angiotensin II act synergistically to preserve and restore blood pressure levels. Decreased circulating vasopressin contributes to adrenal insufficiency via hypothalamic-pituitary-adrenal axis suppression and increased catecholamine resistance to vasopressors. Exogenous vasopressin supplementation in physiologic doses has been shown to improve blood pressure levels and decrease vasopressor needs in patients with septic shock.

Role of the arterial baroreflex in 5-HT1A receptor agonist-mediated sympathoexcitation following hypotensive hemorrhage

5-HT1A-receptor agonists rapidly restore blood pressure and sympathetic activity in conscious rats subjected to hypotensive hemorrhage. 5-HT1A-receptor activation has also been shown to produce a robust increase in baroreceptor-dependent, pulse-synchronous firing of cardiac sympathetic nerves in anesthetized cats. To determine whether 5-HT1A-receptor agonists reverse hemorrhage-induced suppression of sympathetic activity through facilitation of the arterial baroreflex, the effects of the 5-HT1A-receptor agonist, 8-OH-DPAT, were assessed in male Sprague-Dawley rats subjected to sinoaortic baroreceptor denervation and subsequent hypotensive hemorrhage. 8-OH-DPAT produced rapid pressor and sympathoexcitatory responses in hemorrhaged animals that were attenuated, but not blocked, by sinoaortic denervation (SAD) (+49 ± 4 vs. +37 ± 4 mmHg; +165 ± 30 vs. +92 ± 24% baseline, P < 0.01). Spectral analysis of sympathetic activity showed that SAD abolished the 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT)-mediated increases in pulse-synchronous (13 ± 1 vs. 5 ± 1% total power for intact vs. SAD rats, P < 0.01) and Mayer wave-related bursting (18 ± 3 vs. 8 ± 1% total power, P < 0.05). However, 8-OH-DPAT continued to increase total power (+72 ± 22 vs. −63 ± 7% prehemorrhage total power, P < 0.05) and power at the respiratory frequency (35 ± 2 vs. 25 ± 4% total power) in SAD animals. These data indicate that full expression of the sympathoexcitatory effect of 8-OH-DPAT requires a functional arterial baroreflex. However, a portion of the effect is due to activation of arterial baroreflex-independent sympathetic pathways.

Fluid compartments in hemorrhaged rats after hyperosmotic crystalloid and hyperoncotic colloid resuscitation

Postresuscitation organ failure may be associated with detrimental changes in body fluid compartments. We measured how shock and resuscitation acutely alters the interstitial, cellular, and plasma compartments in different organs. Nephrectomized, anesthetized rats were bled to 50 mmHg mean arterial pressure for 1 h, followed by 60 min of resuscitation to restore blood pressure using 0.9% normal saline (NS,n = 10), 7.5% hypertonic saline (HS,n = 8), 10% hyperoncotic albumin (HA, n = 8), or 7.5% hypertonic saline and 10% hyperoncotic albumin (HSA, n = 7). A 2-h 51Cr-EDTA distribution space estimated extracellular fluid volume (ECFV), and a 5-min 125I-labeled albumin distribution space measured plasma volume (PV). Total tissue water (TW) was measured from wet and dry weights; interstitial fluid volume (ISFV) and cell water were calculated. NS resuscitation required 7 times more fluid (50.9 +/- 7.7 vs. 8.6 +/- 0.7 for HA, 5.9 +/- 0.4 for HS, and 3.9 +/- 0.5 ml/kg for HSA), but there were no differences between solutions in whole animal PV, ECFV, or ISFV. Fluid shifts within tissues depended on resuscitation solution and type of tissue. TW was significantly reduced by hypertonic saline groups in heart, muscle, and liver (P < 0.05). ISFV was significantly reduced by HA groups in the skin. In all tissues, mean cell water in groups receiving HS was smaller; this was significant for heart, lung, muscle, and skin. In conclusion, 1) HS solutions mobilize fluid from cells while expanding both PV and ISFV, and 2) TW and cellular water increase with both isotonic crystalloids and hyperoncotic colloids in many tissues.

Effect of the Converting-Enzyme Inhibitor SQ 14 225 (captopril) in Early One-Kidney, One-Clip Hypertension in the Rat

1. Arterial plasma renin activity was significantly elevated in rats with one-kidney, one-clip hypertension of less than 3 weeks duration. 2. Intraperitoneal injection of the angiotensin-converting enzyme inhibitor SQ 14 225 (captopril) caused a dose-related decrease in systolic blood pressure in hypertensive rats. The lowest dose of captopril used (3.5 mg/kg) inhibited conversion of exogenous angiotensin I and maximally potentiated the depressor response to bradykinin, but failed to restore blood pressure to that of the normotensive controls. 3. Removal of the solitary clipped kidney also did not restore blood pressure to normal. Injection of captopril (3.5 mg/kg) 24 h after nephrectomy, when no circulating renin activity was detectable, lowered blood pressure further in hypertensive but not in similarly nephrectomized controls. 4. These results indicate that raised blood pressure in early one-kidney, one-clip hypertension in the rat cannot be entirely attributed to the renin-angioterisin system, even when plasma renin activity is significantly increased. 5. This study has also confirmed a hypotensive action of captopril in anephric rats when plasma renin activity is undetectable.