Spinal Anaesthesia as an Adjunct to General Anaesthesia for Laparoscopic Abdominoperineal Rectal Amputation.

Background: Spinal anaesthesia as an adjunct to general anaesthesia may reduce postoperative pain and opioid consumption after laparoscopic abdominoperineal rectal amputation. We designed a randomized double blinded pilot study with two objectives: 1) to explore potential benefits of spinal anaesthesia as an adjunct to general anaesthesia and 2) to provide power and sample size estimations for potential differences between the groups. Primary outcome measures were postoperative pain and oral morphine equivalent (OMEq) consumption. Methods: Patients scheduled for elective laparoscopic abdominoperineal rectal amputation at the University Hospital of North Norway were randomised to spinal (n=5) or a sham spinal procedure (n=5). Numeric rating scale (NRS) and OMEq were monitored postoperatively for 72 h. Results: Age, sex, body mass index, and ASA were not significantly different between the groups. During surgery, patients in the spinal group received less remifentanil (p=0.06). NRS was lower in the spinal group 1 hr after admittance to the post-anaesthesia care unit (PACU) (p=0.06) and on the first postoperative day at 8 AM (p=0.03). OMEq consumption in the PACU was lower in the spinal group (p=0.008), but no differences between the groups were detected after discharge to the ward. Sample size estimations revealed that eight patients in each group would be needed to study potential NRS differences after admission to the PACU and 23 patients in each group to study potential differences in OMEq consumption on day 1. Conclusion: Spinal anaesthesia as an adjunct to general anaesthesia reduces postoperative pain and opioid consumption after laparoscopic abdominoperineal rectal amputation. Data from the current study should be followed up by a sufficiently powered randomized controlled trial. Clinical Trial Registration: Trial registered at https://clinicaltrials.gov (NCT05406765).

Opioid consumption in two surgical hospital wards. / Forbruk av opioider ved to kirurgiske sykehusavdelinger.

BACKGROUND: The purpose of the study was to document the consumption of opioids in two surgical departments at the University Hospital of North Norway, Tromsø, in the period 2010-17. MATERIAL AND METHOD: The consumption of opioids in the department of gastrointestinal surgery and the department of cardiovascular and thoracic surgery was obtained from Nord hospital pharmacy. All opioids were converted to oral morphine equivalents. RESULTS: The consumption of morphine in the department of gastrointestinal surgery was reduced from 223 835 oral morphine equivalents per year in the period 2010-13, to 147 641 in the period 2014-17. In the department of cardiovascular and thoracic surgery, the yearly consumption of morphine was reduced from 28 652 oral morphine equivalents in the period 2010-13, to 22 945 in the period 2014-17. The consumption of oxycodone in the department of gastrointestinal surgery increased from 210 643 oral morphine equivalents per year in the period 2010-13, to 376 322 in the period 2014-17. In the department of cardiovascular and thoracic surgery, the consumption of oxycodone increased from 28 922 oral morphine equivalents per year in the period 2010-13, to 123 875 in the period 2014-17. In the department of gastrointestinal surgery, the increase was most evident for oxycodone administered intravenously or subcutaneously. In the department of cardiovascular and thoracic surgery, the largest increase was for oxycodone administered orally. INTERPRETATION: The consumption of opioids increased in both departments studied, and oxycodone constituted the largest part of the increase.

Nutritional support for critically ill patients in the intensive care unit. / Ernæring hos kritisk syke intensivpasienter.

Patients in intensive care have increased nutritional needs but are often incapable of eating independently. When should intravenous parenteral nutrition be started, and what is the optimal dose? Here we review the recently updated European guidelines on nutritional support in intensive care patients.

Glycine and hyperammonemia: potential target for the treatment of hepatic encephalopathy.

Hepatic encephalopathy (HE) is a neuropsychiatric disorder caused by hepatic dysfunction. Numerous studies dictate that ammonia plays an important role in the pathogenesis of HE, and hyperammonemia can lead to alterations in amino acid homeostasis. Glutamine and glycine are both ammoniagenic amino acids that are increased in liver failure. Modulating the levels of glutamine and glycine has shown to reduce ammonia concentration in hyperammonemia. Ornithine Phenylacetate (OP) has consistently been shown to reduce arterial ammonia levels in liver failure by modulating glutamine levels. In addition to this, OP has also been found to modulate glycine concentration providing an additional ammonia removing effect. Data support that glycine also serves an important role in N-methyl D-aspartate (NMDA) receptor mediated neurotransmission in HE. This potential important role for glycine in the pathogenesis of HE merits further investigations.

A new non-craniotomy model of subarachnoid hemorrhage in the pig: a pilot study.

Subarachnoid hemorrhage (SAH) from rupture of an intracranial arterial aneurysm is a devastating disease affecting young people, with serious lifelong disability or death as a frequent outcome. Large animal models that exhibit all the cardinal clinical features of human SAH are highly warranted. In this pilot study we aimed to develop a non-craniotomy model of SAH in pigs suitable for acute intervention studies. Six Norwegian Landrace pigs received advanced invasive hemodynamic and intracranial pressure (ICP) monitoring. The subarachnoid space, confirmed by a clear cerebrospinal fluid (CSF) tap, was reached by advancing a needle below the ocular bulb through the superior orbital fissure and into the interpeduncular cistern. SAH was induced by injecting 15 mL of autologous arterial blood into the subarachnoid space. Macro- and microanatomical investigations of the pig brain showed a typical blood distribution consistent with human aneurysmal SAH (aSAH) autopsy data. Immediately after SAH induction ICP sharply increased with a concomitant reduction in cerebral perfusion pressure (CPP). ICP returned to near normal values after 30 min, but increased subsequently during the experimental period. Signs of brain edema were confirmed by light microscopy post-mortem. None of the animals died during the experimental period. This new transorbital injection model of SAH in the pig mimics human aSAH and may be suitable for acute intervention studies. However, the model is technically challenging and needs further validation.

Non-sedation versus sedation with a daily wake-up trial in critically ill patients receiving mechanical ventilation (NONSEDA Trial): study protocol for a randomised controlled trial.

BACKGROUND: Through many years, the standard care has been to use continuous sedation of critically ill patients during mechanical ventilation. However, preliminary randomised clinical trials indicate that it is beneficial to reduce the sedation level. No randomised trial has been conducted comparing sedation with no sedation, a priori powered to have all-cause mortality as primary outcome.The objective is to assess the benefits and harms of non-sedation versus sedation with a daily wake-up trial in critically ill patients. METHODS/DESIGN: The non-sedation (NONSEDA) trial is an investigator-initiated, randomised, clinical, parallel-group, multinational trial designed to include 700 patients from at least six ICUs in Denmark, Norway and Sweden.Inclusion criteria are mechanically ventilated patients with expected duration of mechanical ventilation >24 hours.Exclusion criteria are non-intubated patients, patients with severe head trauma, coma at admission or status epilepticus, patients treated with therapeutic hypothermia, patients with PaO2/FiO2 < 9 where sedation might be necessary to ensure sufficient oxygenation or place the patient in prone position.Experimental intervention is non-sedation supplemented with pain management during mechanical ventilation.Control intervention is sedation with a daily wake-up trial.The primary outcome will be all cause mortality at 90 days after randomization. Secondary outcomes will be: days until death throughout the total observation period; coma- and delirium-free days; highest RIFLE score; days until discharge from the intensive care unit (within 28 days); days until the participant is without mechanical ventilation (within 28 days); and proportion of patients with a major cardiovascular outcome. Explorative outcomes will be: all cause mortality at 28 days after randomisation; days until discharge from the intensive care unit; days until the participant is without mechanical ventilation; days until discharge from the hospital; organ failure.Trial size: we will include 700 participants (2 × 350) in order to detect or reject 25% relative risk reduction in mortality with a type I error risk of 5% and a type II error risk of 20% (power at 80%). DISCUSSION: The trial investigates potential benefits of non-sedation. This might have large impact on the future treatment of mechanically ventilated critically ill patients. TRIAL REGISTER: ClinicalTrials.gov NCT0196768, 09.01.2014.

L-Ornithine phenylacetate reduces ammonia in pigs with acute liver failure through phenylacetylglycine formation: a novel ammonia-lowering pathway.

Glycine is an important ammoniagenic amino acid, which is increased in acute liver failure (ALF). We have previously shown that L-ornithine phenylacetate (OP) attenuates ammonia rise and intracranial pressure in pigs suffering from ALF but failed to demonstrate a stoichiometric relationship between change in plasma ammonia levels and excretion of phenylacetylglutamine in urine. The aim was to investigate the impact of OP treatment on the phenylacetylglycine pathway as an alternative and additional ammonia-lowering pathway. A well-validated and -characterized large porcine model of ALF (portacaval anastomosis, followed by hepatic artery ligation), which recapitulates the cardinal features of human ALF, was used. Twenty-four female pigs were randomized into three groups: (1) sham operated + vehicle, (2) ALF + vehicle, and (3) ALF + OP. There was a significant increase in arterial glycine concentration in ALF (P < 0.001 compared with sham), with a three-fold increase in glycine release into the systemic circulation from the kidney compared with the sham group. This increase was attenuated in both the blood and brain of the OP-treated animals (P < 0.001 and P < 0.05, respectively), and the attenuation was associated with renal removal of glycine through excretion of the conjugation product phenylacetylglycine in urine (ALF + vehicle: 1,060 ± 106 µmol/l; ALF + OP: 27,625 ± 2,670 µmol/l; P < 0.003). Data from this study provide solid evidence for the existence of a novel, additional pathway for ammonia removal in ALF, involving glycine production and removal, which is targeted by OP.

[Intensive care of patients with acute liver failure]. / Intensivbehandling av voksne med leversvikt.

BACKGROUND: Acute liver failure and acute decompensated chronic liver failure are two diseases that demand extensive knowledge of etiology and triggering factors, pathophysiology, diagnosis, prognosis and recommended guidelines for treatment. The article defines the diseases, discusses etiological factors, treatment strategies, indications for referral to the transplantation unit at Rikshospitalet and prognostic factors of importance. MATERIAL AND METHODS: The basis for this article is literature identified through a non-systematic search in PubMed and the authors' clinical experience and experimental research within the field. RESULTS: In the Western world paracetamol poisoning and toxic reactions to other drugs are the most common triggering factors for acute liver poisoning in adults. Patients can quickly develop multi organ failure requiring advanced intensive care. The most common complications are hepatic encephalopathy, acute renal failure and coagulation disturbances. Acute decompensated chronic liver failure strikes patients with known liver disease and is most often triggered by inflammation, infection, gastrointestinal bleeding, drugs, traumas or disturbances in acid/base/electrolyte balance. Early diagnosing of triggering factors and intensive medical supportive treatment is especially important. Acute renal failure indicates a very bad prognosis. INTERPRETATION: Patients diagnosed with acute liver failure or acute decompensated chronic liver failure remain a clinical challenge. Optimal treatment requires extensive knowledge of pathophysiological mechanisms and treatment strategies.

Neuropathological changes in the brain of pigs with acute liver failure.

OBJECTIVE: Cerebral edema is a serious complication of acute liver failure (ALF), which may lead to intracranial hypertension and death. An accepted tenet has been that the blood-brain barrier is intact and that brain edema is primarily caused by a cytotoxic etiology due to hyperammonemia. However, the neuropathological changes in ALF have been poorly studied. Using a well characterized porcine model we aimed to investigate ultrastructural changes in the brain from pigs suffering from ALF. MATERIALS AND METHODS: Sixteen female Norwegian Landrace pigs weighing 27-35 kg were randomised into two groups: ALF (n = 8) and sham operated controls (n = 8). ALF was induced with an end-to-side portacaval shunt followed by ligation of the hepatic arteries. Biopsies were harvested from three different areas of the brain (frontal lobe, cerebellum, and brain stem) following eight hours of ALF and analyzed using electron microscopy. RESULTS: Profound perivascular and interstitial edema were found in all three areas. Disruption of pericytic and astrocytic processes were seen, reflecting breakdown/lesion of the blood-brain barrier in animals suffering from ALF. Furthermore, neurons and axons were edematous and surrounded by vesicles. Severe damage to Purkinje neuron (necrosis) and damaged myelin were seen in the cerebellum and brain stem, respectively. Biopsies from sham operated animals were normal. CONCLUSIONS: Our data support the concept that vasogenic brain edema plays an important role in the development of intracranial hypertension in pigs with ALF.

L-ornithine phenylacetate attenuates increased arterial and extracellular brain ammonia and prevents intracranial hypertension in pigs with acute liver failure.

UNLABELLED: Hyperammonemia is a feature of acute liver failure (ALF), which is associated with increased intracranial pressure (ICP) and brain herniation. We hypothesized that a combination of L-ornithine and phenylacetate (OP) would synergistically reduce toxic levels of ammonia by (1) L-ornithine increasing glutamine production (ammonia removal) through muscle glutamine synthetase and (2) phenylacetate conjugating with the ornithine-derived glutamine to form phenylacetylglutamine, which is excreted into the urine. The aims of this study were to determine the effect of OP on arterial and extracellular brain ammonia concentrations as well as ICP in pigs with ALF (induced by liver devascularization). ALF pigs were treated with OP (L-ornithine 0.07 g/kg/hour intravenously; phenylbutyrate, prodrug for phenylacetate; 0.05 g/kg/hour intraduodenally) for 8 hours following ALF induction. ICP was monitored throughout, and arterial and extracellular brain ammonia were measured along with phenylacetylglutamine in the urine. Compared with ALF + saline pigs, treatment with OP significantly attenuated concentrations of arterial ammonia (589.6 +/- 56.7 versus 365.2 +/- 60.4 mumol/L [mean +/- SEM], P= 0.002) and extracellular brain ammonia (P= 0.01). The ALF-induced increase in ICP was prevented in ALF + OP-treated pigs (18.3 +/- 1.3 mmHg in ALF + saline versus 10.3 +/- 1.1 mmHg in ALF + OP-treated pigs;P= 0.001). The value of ICP significantly correlated with the concentration of extracellular brain ammonia (r(2) = 0.36,P< 0.001). Urine phenylacetylglutamine levels increased to 4.9 +/- 0.6 micromol/L in ALF + OP-treated pigs versus 0.5 +/- 0.04 micromol/L in ALF + saline-treated pigs (P< 0.001). CONCLUSION: L-Ornithine and phenylacetate act synergistically to successfully attenuate increases in arterial ammonia, which is accompanied by a significant decrease in extracellular brain ammonia and prevention of intracranial hypertension in pigs with ALF.

[Disturbances in ammonia metabolism in hepatic failure]. / Forstyrrelser i ammoniakkmetabolismen ved leversvikt.

BACKGROUND: Serious hepatocellular dysfunction leads to disturbances in the ammonia metabolism and increases the risk for development of hepatic encephalopathy. The present paper describes pathophysiological patterns for development of hyperammonemia in patients with liver diseases and discusses the rationale for novel ammonia lowering strategies. MATERIAL AND METHODS: The present paper is based on experimental research performed in a porcine model of acute liver failure and a literature search in Pubmed. RESULTS: Under normal conditions the intestines and the kidneys are the main ammonia producing organs, whereas the liver and skeletal muscles are the major ammonia consuming organs. Small and large intestines contribute equally to the release of ammonia. Development of intra- and extra hepatic portasystemic shunts, impaired urea synthesis, and reduced hepatic perivenous glutamine synthesis capacity, contribute to the development of hyperammonaemia with hepatic failure. The kidneys are quantitatively as important as the portal drained viscera in ammonia production, but can adapt to hyperammonaemia by reducing the production of ammonia to the blood and at the same time increase its excretion in urine. Furthermore, the lungs are metabolically active, but their role in hyperammonaemia remains unsettled. Skeletal muscle contributes to reducing the ammonia level in the body through synthesis of glutamine from equimolar quantities of glutamate and ammonia. INTERPRETATION: Current therapeutic recommendations on protein restriction, use of antibiotics and lactulosis to patients with hepatic failure are not sufficiently documented. There is a need for development of novel ammonia lowering strategies.

Endothelium-derived hyperpolarization factor (EDHF) is up-regulated in a pig model of acute liver failure.

BACKGROUND: Acute liver failure (ALF) is hemodynamically characterized by hyperdynamic circulation, but the pathophysiologic mechanisms underlying these disturbances are not known. The purposes of the present experiments were: to study systemic and peripheral hemodynamics in vivo, to measure changes in vascular reactivity in vitro, and to determine the role of endothelium-dependent vasodilator pathways in a well-validated porcine model of ALF. METHODS: Landrace pigs (24-29 kg) were allocated to sham operation (n=8) or ALF induced by hepatic devascularization (n=9). Systemic and regional hemodynamics were monitored. Femoral artery rings were prepared for isometric tension recordings 8 h after ALF induction. Contractile responses to phenylephrine were assessed in ring segments of endothelium-intact femoral arteries in the absence or presence of inhibitors of endothelium-derived hyperpolarizing factor, nitric oxide synthase, cyclooxygenase and heme oxygenase pathways. RESULTS: Pigs with ALF developed a hyperdynamic circulation. Cardiac index increased (PGT<0.001), while mean arterial pressure (PGT=0.012) and systemic vascular resistance decreased (PGT<0.001) in this group. Femoral artery blood flow decreased in controls, while it remained unchanged in ALF (PGT=0.010). Accordingly, vascular resistance across the hind leg was significantly decreased (PGT<0.001) in ALF. The combination of Ca2+-activated potassium channel inhibitors charybdotoxin and apamin, which block the release of endothelium-derived hyperpolarizing factor, increased the contraction force (ANOVA, PGT=0.05) and Emax (P=0.01) to phenylephrine in ALF. In contrast, inhibitors of nitric oxide synthase, cyclooxygenase and heme oxygenase pathways did not increase isometric contraction force. CONCLUSIONS: Endothelium dependent hyperpolarization of vascular smooth muscle contributes to the development of hyperdynamic circulation in ALF.