Thromboelastography and Thromboelastometry in Patients with Sepsis - A Mini-Review-Juniper Publishers

Introduction

Coagulopathy is a common finding in patients with sepsis and is considered to be a risk factor for mortality [1]. Mechanisms like imbalance between coagulation and fibrinolysis have been attributed to coagulopathy in sepsis. The spectrum of coagulopathy can range from a hypercoagulable state to a hypocoagulable state [2]. Conventional coagulation assays (CCAs) like prothrombin time (PT) and activated partial thromboplastin time (aPTT) are routinely done to assess coagulation status in patients with sepsis. However, these coagulation tests have certain inherent limitations associated with them [3]. These limitations include their inability to detect hypercoagulable state and also cannot assess the fibrinolytic system. Rotational thromboelastography (TEG) and thromboelastometry (ROTEM) evaluate whole clot formation and can be useful point-of-care tests [3]. There is ongoing research to establish the efficacy of TEG/ROTEM over conventional coagulation tests in detection of hypo- or hypercoagulable states in sepsis and in guiding transfusion practices [4].

Basic principles of conventional thromboelastography (TEG®) and thromboelastometry (ROTEM®): [3,4]. The basic principle of functioning is similar in both thromboelastography (TEG®) and thromboelastometry (ROTEM®) with only subtle differences. Rotational thromboelastograph (TEG®) analyzer has a pin and an oscillating cup. However, in thromboelastometry (ROTEM®), the pin rotates and the cup remains fixed. Once blood begins to clot, fibrin strands are formed which influence the movement between the cup and the pin. This process is detected electromechanically and finally presented as a computerized tracing known as the thromboelastograph. Thromboelastograph is a waveform which depicts certain parameters that reflect different phases of the clotting process. These parameters are mentioned below:

An overview of TEG/ ROTEM with terminologies is presented below

A. Clot formation

Reaction time (R): R time represents the time of latency from start of test to the first evidence of clot or initial fibrin (or time taken for clot to achieve an amplitude of 2 mm) and it correlates with the level of clotting factors. In ROTEM®, R time is represented by clotting time (CT).

B. Clot kinetics

K time: K time is a measure of clot strength and it reflects the time taken for clot to reach an amplitude of 20 mm from the start of clot formation. It is recorded from the end of R time. In ROTEM®, K time is represented by clot formation time (CFT).

α angle: α angle is the angle along horizontal axis of thromboelastograph and it measures the speed at which fibrin build up and cross linking takes place. Hence, it assesses the rate of clot formation. a angle is the common terminology for this angle in both conventional thromboelastography (TEG®) and thromboelastometry (ROTEM®).

Either K time (or CFT) and a angle correlate with fibrinogen levels

i. Clot strength

Maximum amplitude (MA): MA measures the ultimate strength of fibrin clot and correlates with the level of platelets. In ROTEM ®, MA is represented by maximum clot firmness (MCF).

ii. Coagulation index (CI)

CI is calculated by a complex mathematical formula calculated from R, K, α and MA and has a normal reference range between -3 to 3. It is an overall indicator of coagulation and represents hypocoagulable (CI<-3), normocoagulable (CI -3 to 3) or hypercoagulable states (CI >3).

iii. Clot lysis (Fibrinolysis)

A30: A30 is the amplitude at 30 minutes post-MA (in both conventional thromboelastography and thromboelastometry).

Lysis index (CL 30%): CL 30 indicates the percentage decrease in amplitude 30 minutes post-MA. LY 30% represents the lysis index in thromboelastometry.

Estimated platelet lysis (EPL %): EPL is the computer prediction of diminution of amplitude 30 seconds post-MA and it is the earliest indicator of abnormal clot lysis (in bothconventional thromboelastography and thromboelastometry).

Hypocoagulability is defined as increased CT/R and CFT/K times and/or decreased MCF/MA and alpha angle.

Hypercoagulability is defined as decreased reaction times (CT/R and CFT/K times) and increased clot formation (increased alpha angle or high maximal amplitude (MCF/MA).

The thromboelastograph parameters are also useful in the diagnosis and management of hypocoagulability and hypercoagulability, identification of primary and secondary hyperfibrinolysis and differentiating between medical and surgical causes of bleeding (Table 1).

Studies on the ability of ROTEM® and TEG® to detect sepsis-induced coagulopathy or disseminated intravascular coagulation (DIC)

Results of TEG®/ROTEM® in sepsis have varied widely across the studies. Some patients have shown distinct hypocoagulabilty while others have shown a predominant hypercoagulable pattern. There are several reasons to explain this lack of uniformity in test results. The timing of measurement has varied widely in the studies. The initial phase of sepsis is characterized by formation of microvascular thrombi and the later phase manifests as a hypocoagulant phase secondary to consumptive caogulopathy. So, the timing of measurement has a bearing on test results. This heterogeneity can also be explained by the difference in disease severity of study population. Interestingly, there is no universally validated reference value and definition of hypocoagulability and hypercoagulability of ROTEM®/TEG® in the available studies. Overall, if sepsis- induced coagulopathy was present, ROTEM®/TEG® could detect it in 43-100% patients.

Some of these studies are mentioned below

Collins and co-workers investigated 38 patients with severe sepsis by performing global tests of haemostasis and compared them with 32 controls. They found that although patients with severe sepsis had a delayed activation of haemostasis but once initiated, thrombin generation and clot formation were normal or even enhanced in this group. Routine coagulation assays, which measure only the initiation of clotting process and not its propagation, poorly evaluate the coagulation capacity of such patients [8].

Role of ROTEM® and TEG® for anticoagulant treatment in sepsis

There are only few studies attending to this area with very small series of patients [11].

Role of ROTEM® and TEG® in prediction of outcome in sepsis

Hypocoagulability has been found to be an independent predector of poor outcome in some studies as mentioned below:

Daudel and co-workers in 2009 studied 30 patients with sepsis. Routine clotting tests and thromboelastometry (ROTEM®) were done every 12 hrs during first 48 hrs of admission, and finally at discharge from ICU. It was observed that patients with more severe organ failure (SOFA>10) had higher CFT (125±76 sec vs 69±27 sec) and lower MCF (57±11 mm vs 69±27 mm) as compared to those with less severe organ failure (SOFA<10). The values changed significantly with the intensity of sepsis. Improved organ dysfunction upon discharge from ICU  was associated with shortened coagulation time, accelerated clot formation and increased firmness of blood clot [12].

Adamzik and co-workers in 2011 performed a study in 98 patients with severe sepsis to investigate the role of thromboelastometry (ROTEM®) as a potential predictor of 30-day survival in severe sepsis and compared ROTEM® with simplified acute physiology II (SAPS II) and SOFA scores. CT, CFT, a angle, MCF and SAPS II and SOFA scores were recorded on the day of diagnosis of sepsis. Mean CFT was significantly prolonged (276 ± 194 sec vs. 194 ± 109 sec) and both MCF (52.7 ± 12.1 mm vs. 57.3 ± 11.5 mm) and a angle (53.4 ± 12.8 degrees vs. 58.9 ± 11.8 degrees, P = 0.028) were significantly reduced in non-survivors. SAPS II and SOFA scores were not different between survivors and non-survivors [13].

Ostrowsky and co-workers in 2013 studied 50 patients with severe sepsis. Patients were divided into 3 groups on the basis of MA value of TEG® on admission: hypocoagulable MA, normocoagulable MA or hypercoagulable MA. Patients progressing to hypocoagulability had higher SOFA and DIC scores and they also showed a higher early mortality [14].

Conclusion

In summary, both thomboelastography (TEG®) and thromboelastometry (ROTEM®) seem to have a promising role in the evaluation of coagulation abnormalities in sepsis. But the available studies in sepsis show heterogeneous results and are of limited quality [4].

TEG/ROTEM measurements in sepsis can show both hypo- and hypercoagulability. Hypercoagulability is seen more in acute phase of sepsis. Timing can influence the results because sepsis is a dynamic process. Sequential measurements of TEG/ ROTEM can enlighten us more about coagulation derangements associated with sepsis. The current evidence is limited due to heterogeneity, small sample size, lack of standardized definitions for hypo- and hypercoagulable states. Larger trials can establish the utility of TEG/ROTEM to detect coagulation abnormalities to diagnose DIC and to guide transfusion therapy.

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Negative Inspiratory Pressure as a Predictor of Weaning Mechanical Ventilation-Juniper Publishers

Introduction

Mechanical ventilation (MV) is a widely used resource within intensive care units (ICUs) for the maintenance of the lives of critically ill patients. However, its prolongation is associated with several complications, such as pneumonia, hemodynamic disorders, lung injury and diaphragmatic dysfunction; the latter defined as the set of structural and functional alterations produced by the inactivity of the diaphragm muscle during MV [1,2].

Several investigations developed since the 1990s on the impact of MV have been able to show changes in the diaphragm as a consequence of the prolonged use of positive pressure in the airway [2-5]. These changes reduce and modify the correct diaphragmatic functioning, making the weaning process more complicated and delayed due to the difficulty for the patient to spontaneously assume ventilatory work [2,3]. This translates into an increase in the number of hospital stay days, and consequently, costs in health services [6,7].

For all of the above, early ventilatory weaning is established as one of the main objectives in the management of the critical patient and its initiation should be considered from the moment the cause of the use of ventilatory support improves [8]. The success of weaning is defined as the maintenance of spontaneous breathing for at least 48 hours after discontinuation of MV. If the need to return to artificial ventilation arises during this period, it may be thought that weaning has failed [9]. It is considered that approximately 55% of the patients manage to pass this process without difficulties [10]; However, between 20 and 30% of the patients who are weaned from the ventilator present respiratory complications after extubation, requiring the reinstatement of the artificial airway [11].

Weaning failure can be due to several factors, summarized in four groups: alterations in gas exchange, hemodynamic instability, respiratory pump failure and psychological dependence on the ventilator [12]. This fact occurs in many cases because weaning is based on clinical judgments and individualized styles, behaviors that favor the prolongation of MV time [13]. Herein lies the importance of establishing a protocol of weaning and extubation systematically, integrally and preferably universal within the ICUs.

However, most of these criteria are not always statistically reliable because they present low sensitivity and specificity, and may give rise to the appearance of false positives and false negatives. In summary, precise parameters included within the weaning protocol do not always exist to predict the success or failure of weaning and extubation [11].

One of the predictors that has been contemplated in recent years to estimate the success of weaning is the maximum inspiratory pressure, commonly known as PIM, defined as maximum pressure that can be generated against an occluded airway for 20 seconds from the capacity Functional residual; In this sense, can be considered as a direct marker of inspiratory muscle function, and in particular, of diaphragmatic force [14].

The first time we talked about IMP measurement in critically ventilated patients was in 1973, when Sahn and Cols.la included within the extubation criteria, along with the value of minute ventilation and maximum voluntary ventilation. The research concluded that patients with values >30cm H20 are able to maintain their mechanical ventilation spontaneously [15]. On the other hand, in 1975 Feeley et al. [16] reported that the inspiratory force should be ≥20cm H20 to interrupt assisted ventilation.

In 1993, Strickland and Hasson developed an automatic weaning stool system for postoperative patients. Within the inclusion criteria to begin weaning, they added the Negative Inspiratory Force (NIF) denomination that until then had not been handled to refer to maximal inspiratory pressure [17].

Yang and Tobin performed a prospective study where they established the predictive indexes of the results of ventilatory weaning, taking NIF as one of them. In their research, they determined that inspiratory pressure is a better predictor of failure than of weaning success [18]. In contrast, Ebeid and Cols. Deduced in 2013 that NIF is a good predictor of weaning success [19].

It has been established that a NIF ≥-20 or -25cm H2O is adequate to initiate ventilatory weaning; With a NIF>-30cm H2O, there is a 93% chance of successful weaning [20,21], and on the contrary, with a NIF of >-15 or >-10cm H2O, patients are unable to breathe on their own (twenty-one). Parallel to this, values of -33cm H20 with a 50% mortality decrease -28cm H20 with 42% and -26cm H20 with 32% respectively have been associated [22].

Recently, we conducted a study with Colombian population, considering the measurement of NIF as a parameter of evaluation of diaphragmatic dysfunction in MV, which is being submitted for publication, considering that its use in patients submitted to MV is possible thanks to its Incorporation into state-of-the- art mechanical fans. The measurement is done by an invasive technique, simple and well tolerated by the patients. Thus, the value of NIF is presented as an effective alternative to take into consideration, both to assess the degree of diaphragmatic injury, to initiate weaning and to perform extubation.

Although NIF seems to be the most adequate measure to quantify the degree of pulmonary dysfunction in patients with ventilatory support, depending on the probability of success or failure of weaning, the information that can be found on its application within critical care remains limited and discordant, Which makes it necessary to carry out more research in which NIF is considered as a parameter of evaluation for respiratory dysfunction within a structured battery or as a potential extubation criterion.

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Safest Anesthetic Technique for Hip Fractures in Elderly-Juniper Publishers

Background

There is high incidence of perioperative complications in hip surgeries after femoral neck fractures in older age group.

Objective

In this review, we try to detect the safest anesthetic technique for those patients.

Introduction

Hip fracture is a worldwide problem affecting 1.6million and will affect 2.6 annually by 2025 [1].Hip  fractures are associated with high risk of morbidity and mortality, approximately 1-6% of patients will die during their hospital stay [2-4], 4-10% will die with in 30 days of their admission [5], and 18%- 28% of the patients die with in one year of their fractures [6] this is mainly due to pulmonary and cardiovascular complications [7]. Postoperative delirium is a frequent complication in elderly patients with hip fractures and the incidence is varying between 16% and 62% [8]. Patients with femoral neck fracture can experience delirium three times more than patients undergoing non orthopedic surgery [9]. Postoperative delirium is associated with high morbidity and mortality and prolonged hospitalization with subsequent increased suffering and cost [10]. There are many risk factors associated with postoperative morbidity and mortality in such age group of patients. Adequate preoperative treatment of respiratory problems (COPD, asthma) and prevention of postoperative cardiovascular complications (hypotension, hypertension, arrhythmia, ischemia, heart failure) may be the most important factor in reducing postoperative mortality after hip fracture surgery [11]. Cardiovascular, respiratory and neurological complications are well correlated to age, preoperative bedridden state, neurological comorbidities, preoperative delirium, and frequent intraoperative hypotension.

Anesthesia type

The influence of anesthesia type on mortality and morbidity in hip fracture surgery is certainly a controversial issue in the literature. Regional anesthesia has significantly reduced incidences of deep venous thrombosis, surgical site infection, pulmonary complications, and amount of blood loss. General anesthesia has a lower incidence of hypotension and cerebrovascular accidents [12]. A retrospective cohort study based on a nation wide sample of hospital admissions found that, there was no significant difference in risk of mortality with type of anesthesia in patients undergoing hip fracture surgery [13]. Regarding thirty days mortality another study found that, spinal anesthesia was associated with significantly lower incidence of thirty days complications than general anesthesia in hip fracture surgery [14]. Liu et al. [15] found that there was no significant difference in post-operative mortality and complications between general anesthesia and peripheral nerve blocks in these cases [15]. Jin et al. [16] found that there was no significant difference between peripheral nerve blocks and epidural anesthesia in hip fracture surgery regarding postoperative mortality and complications [16]. Continuous spinal anesthesia and ultrasound guided combined psoas compartment-sciatic nerve block (PCSNB) produced satisfactory quality of anesthesia in elderly high risk patients of hip replacement surgery but hemodynamic changes were fewer in us guided PCSNB [17].

Conclusion

A variety of appropriate anesthetic techniques can be used according to the patient individual condition regarding patient choice, comorbidities, psychological make up, anesthetist previous experience, surgical procedure, hospital facilities including funds available and postoperative care.

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Understanding the Three Principal Goals of Clinical Airway Management-Juniper Publishers

Introduction

There are three main goals of clinical airway management-appropriate oxygenation, appropriate ventilation, and protection of the airway from injury. Let's briefly look at each of these goals.

Oxygenation

Oxygenation is controlled via the concentration of oxygen (fraction of inspired oxygen - Fi02) delivered to the patient, although "PEEP" adjustment can be equally important to improve oxygenation in ventilated patients with acute lung injury (PEEP or positive end expiratory pressure, is the minimum lung distending pressure over expiration during positive pressure ventilation; it is usually set between 2 and 5 cm H2O in patients with normal lungs). The minimum oxygen concentration used during general anesthesia is usually 0.3 (30%) and can be increased to 1.0 (100%) by decreasing the concentration air administered (or of nitrous oxide (N2O) in patients where this is used during general anesthesia). As a rough rule one adjusts FI02 (and PEEP in specialized settings) to keep arterial oxygen saturation above 94% (using a pulse oximeter) or keeping the arterial oxygen tension (PaO2) between 100 and 150 mm Hg in patients where arterial lines are available for arterial blood gas analysis.

Ventilation

In spontaneous ventilation (negative pressure ventilation), negative pressure inside the lungs from diaphragmatic flattening draws in air. It is important that clinicians recognize when a patient is not adequately ventilating; reasons could include inadequate respiratory effort (e.g., from excessive opioids, partial or complete airway obstruction (e.g., from airway edema) or both. If the patient is not breathing adequately one generally starts with a simple maneuver such as a chin lift or jaw thrust to help open the airway, with positive pressure ventilation with a bag-mask device being the next step if this intervention proves to be ineffective. Concurrently, in cases of suspected airway obstruction, the clinician physician must take measures to alleviate the obstruction. Prolapse of the tongue into the posterior pharynx due to loss of tone in the submandibular muscles is a frequent cause in unconscious patients. While a chin lift or jaw thrust is often sufficient adequate chest ventilation, some cases require that an artificial airway be placed (discussed later). Also, if one hears "gurgling" with breathing the oropharynx should be suctioned.

With positive pressure ventilation (PPV) gas is forced into the lungs using a positive pressure source such as a manual resuscitator or an automatic ventilator. PPV is often facilitated with muscle relaxation ("paralytics") but it is not generally necessary. With conventional ventilators, ventilation is determined by adjusting two parameters: tidal volume (TV) and respiratory rate (RR). To ventilate a typical patient using a ventilator, start with TV=7- 10ml/kg and RR=10/min and then adjust according to obtained end-tidal CO2 levels (ETCO2) (obtained via capnography) or from arterial carbon dioxide tension (PaCO2) measurements. On some older anesthesia machines the tidal volume delivered depends on the total fresh gas flow (FGF), often set between 1 and 6 liters/min (flows of 1-2 liters/min are most economical).

Protection of the Airway from Injury

A final important goal of clinical airway management is preventing lung injury that may result from various causes such as [1] gastric contents spilling into the lungs (aspiration pneumonitis) [1], [2] retention of secretions that may lead to pneumonia, or [3] partial lung collapse (atelectasis). The prevention of aspiration in unconscious patients (generally those under general anesthesia or patients with a head injury) is usually achieved by using a cuffed endotracheal tube; unintubated patients may develop deadly aspiration pneumonitis and ARDS (adult respiratory distress syndrome) [2] if stomach contents spill into the lungs (especially if the pH is <2.5 or volume >25ml). Patients at risk of aspiration with the induction of general anesthesia are usually managed with either a rapid sequence induction (RSI) or with awake intubation.

Finally, note that lung ventilation itself can sometimes be the cause of lung injury ("ventilator-associated lung injury") [3,4]. Numerous studies have proven that imprudent lung ventilation can cause inflammatory damage to the lungs from repetitive closing and reopening of the alveoli, barotrauma (trauma from excessive pressure), and volutrauma (trauma from excessive lung expansion). Even worse, induced systemic inflammatory changes from imprudent ventilation may even cause dysfunction or failure in other organs.

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Dynamic Parameters do not Predict Fluid Responsiveness in Ventilated Patients with Severe Sepsis or Septic Shock-Juniper Publishers

Abstract

The dynamic parameters, stroke volume variation (SVV) and pulse pressure variation (PPV), are used to guide fluid resuscitation in ventilated patients. We investigated whether SVV, PPV and pleth variability index (PVI), an automatic measurement of the plethysmographic waveform amplitude changes, can be used to predict fluid responsiveness in ventilated patients with severe sepsis or septic shock. We measured cardiac index, (CI, transpulmonary thermodilution PiCCO2) SVV, PPV, global end-diastolic index (GEDI), central venous (CVP), arterial blood pressure and PVI (Masimo Radical 7) before and after infusion of 500ml Gelofusine® over 30min in 31 deeply sedated ventilated patients (tidal volume 8ml/kg) with severe sepsis and septic shock. We obtained one full set of measurements in 30 patients. 10 patients increased CI by at least 15% ("responders”), 20 patients were "non-responders”. Baseline haemodynamic variables were not significantly different between both groups. The area under the receiver operating curves (mean, SE) were 0.68 (0.11) for SVV, 0.66 (0.12) for PPV, 0.59 (0.12) for PVI, 0.55 (0.12) for GEDI and 0.75 (0.09) for CVP We concluded that none of the investigated dynamic parameters could reliably predict fluid responsiveness in ventilated patients with severe sepsis and septic shock in our study.

Introduction

Shock in sepsis results from vasodilatation and a reduction of effective intravascular volume. Its treatment, among others, includes optimal fluid resuscitation. Both over and under resuscitation can worsen outcome in these patients [1]. Routine clinical examination and static indicators of cardiac preload such as central venous pressure (CVP), pulmonary capillary wedge pressure (PCWP), or left ventricular (LV) end diastolic area, are poor predictors of fluid responsiveness [1,2]. Recent studies have shown that respiratory variations in the dynamic indicators of LV stroke volume (SV), namely pulse pressure variation (PPV) and SV variation (SVV) are more reliable predictors of fluid responsiveness in ventilated septic patients [3-5]. Respiratory changes in the amplitude of the plethysmographic pulse wave (ΔPOP) have been shown to be as accurate as PPV in predicting fluid responsiveness in ventilated septic patients [5]. Pleth variability index (PVI), an automatic and continuous monitor of ΔPOP, has been demonstrated to predict fluid responsiveness in ventilated patients undergoing general anaesthesia [6], and in critically ill ventilated patients with circulatory insufficiency [4]. However, it is unclear whether PVI specifically predicts fluid responsiveness in ventilated patients with severe sepsis or septic shock. Therefore, we conducted a prospective, non-randomised, nonblinded observational study to compare the ability of multiple dynamic and static cardiovascular parameters to predict fluid responsiveness in mechanically ventilated patients with severe sepsis or septic shock.

Materials and Methods

The study protocol for this observational study was approved by both national and local ethics committees and was conducted in accordance with the Declaration of Helsinki of the World Medical Association. A valid informed and written consent was obtained from patients' next of kin, after detailed explanation of the protocol, prior to enrolment into the study. Retrospective consent was obtained from all patients who survived to discharge from intensive care and regained mental capacity.

Patients

Thirty-one adult non-pregnant patients who required sedation and controlled mechanical ventilation for treatment of severe sepsis or septic shock, as defined by the International Sepsis Definitions Conference [7], were enrolled in the study. Patients were subjected to a fluid challenge (500ml of Gelofusine® administered over 30min) if they showed at least one sign of inadequate tissue perfusion (systolic blood pressure less than 90mmHg, urine output less than 0.5mlkg- 1h-1 for more than 2 hours, tachycardia greater than 100 beats per minute or capillary refill greater than 2 seconds). Patients were sedated with a continuous infusion of Protocol and Alfentanil. Infusions were titrated to achieve a Richmond Agitation Sedation Scale of -3. Patients were ventilated with a pressure controlled mode (BIPAP mode, EVITA 4 XL, Draeger, Germany) with a tidal volume of 8ml/kg estimated ideal body weight and a positive end-expiratory pressure of not more than 15cm H20. Respiratory rate was adjusted to achieve an arterial partial pressure of CO2 of 4.8-6kPa. The FiO2 was titrated to achieve an arterial saturation of >92%, the ratio of inspiratory versus expiratory time did not exceed 1:1. Exclusion criteria included any spontaneous breathing activity, a known allergy to Gelofusine®, any cardiac rhythm other than sinus rhythm, contraindications for a fluid challenge (PaO2/FiO2 less than 13.3kPa, pulmonary oedema on chest X-ray), patients unable to lie supine or peripheral vasoconstriction causing obliteration of the plethysmographic signal.

Haemodynamic monitoring

Invasive haemodynamic monitoring was performed by using either a 20cm 5-Fr thermistor-tipped arterial thermodilution catheter (Pulsiocath, Pulsion Medical Systems AG, Germany) inserted into a femoral artery or by using a 22cm 4-Fr thermistor-tipped arterial thermodilution catheter (Pulsiocath, Pulsion Medical Systems AG, Germany) inserted into a brachial artery. The tip of a central venous catheter (Arrow International Inc., Reading, PA, USA) was positioned in the superior cava vein confirmed by X-ray examination. Central venous blood gas samples were taken pre and post fluid challenge (ABL 725, Radiometer, Copenhagen, Denmark). The arterial catheter was connected to an advanced haemodynamic monitor (PiCCO2®, Pulsion Medical Systems AG, Munich, Germany). Thermodilution was performed using at least three cold fluid boluses randomly throughout the respiratory cycle and was repeated within five minutes prior to and five minutes post fluid administration. The patient was positioned supine for all measurements. Electrocardiogram, arterial blood pressure, CVP and arterial oxygen saturation (SaO2) were continuously monitored (Spectrum Monitor, Datascope Corporation, Montvale, NJ, USA) and all recordings were taken at end-expiration. A pulse oximeter probe (LNCS® Adtx, Masimo Corp., USA) was attached to the index finger of the right hand and wrapped to prevent outside light from interfering with the signal. This pulse oximeter probe was connected to the Masimo Radical 7 monitor (Masimo SET, Masimo Corp., Irvine, CA, USA) displaying perfusion index and Pleth Variability Index (PVI).

Conduct of the study

After ensuring at least a 5-minute period of haemodynamic stability, the first set of measurements was obtained. This was followed by a fluid bolus of 500ml Gelofusine® infused intravenously over 30min. The second set of measurements was obtained 5min after the fluid infusion was completed. Ventilator settings and dosages of inotropic, vasoactive and anaesthetic drugs were held constant throughout the measurements. At each step of the protocol, the following variables were recorded: Heart rate (HR), systolic, diastolic and mean arterial pressure (MAP), CVP, central venous oxygen saturation (ScvO2), SV, SV index (SVI), CO, cardiac index (CI), global end-diastolic index (GEDI), SpO2, PPV, SVV and PVI. All patients were kept in a supine position during the entire period of the study. Only one full set of data was obtained and analysed per patient.

Statistics

In accordance with previous studies [8], we took the criteria of a 15% increase in CI in response to the fluid challenge to differentiate responders from non-responders to fluid. The normality of distribution of data was tested using the Kolmogorov-Smirnov test. Parametric data are presented as mean with standard deviation or standard error and non- parametric data as median with inter-quartile range (IQR).

We compared non-parametric haemodynamic data before and after volume expansion in responder and non-responder patients using the Mann-Whitney U test. Wilcoxon signed rank tests were used to compare the response to fluid in responders and non-responders, respectively. Receiver operating characteristic (ROC) curves comparing the ability of CVP, SVV, PPV, GEDI and PVI at baseline to discriminate between responders and non-responders to volume expansion were generated varying the discriminating threshold of each parameter. Using the results from previously published studies [3], we conducted a priori power calculation which showed that 31 patients were necessary to detect differences of 0.1 between areas under the ROC curves with a 5% two-sided type I error and 80% power. A p-value less that 0.05 was considered as significant. All statistical analyses were performed using IBM SPSS Statistics for Windows, Version 20.0.

Results

Thirty-one patients were recruited. One patient declined to provide consent retrospectively. Complete sets of data were analysed for the remaining 30 patients. Baseline characteristics, as well as respiratory variables and vasopressor/inotropic requirements were not statistically different between responders and non-responders (Table 1). Ten patients increased CI by 15% or more after volume expansion and were classified as responders. 20 patients were classified as nonresponders. There was no statistically significant difference in any haemodynamic variable at baseline between the two groups (Table 2). Both responders and non-responders increased CVP and decreased PPV in response to the fluid challenge (Table 3 & 4). Only responders showed a statistically significant increase in GEDI (Table 3). Receiver operating characteristic curves (ROC) comparing the ability of CVP, SVV, PPV, PVI and GEDI to predict fluid responsiveness is shown in (Figure 1). The area under the receiver operating curves (mean, SE) were 0.68 (0.11) for SVV, 0.66 (0.12) for PPV, 0.59 (0.12) for PVI, 0.55 (0.12) for GEDI and 0.75 (0.09) for CVP (Table 5, Figure 1).

BSA: Body Surface Area; FiO2- Fraction of Inspired Oxygen; PEEP Peak End Expiratory Pressure; PaO2 Partial Pressure of Arterial Oxygen; PaO-2/ FiO2 Ratio of Partial Pressure of Arterial Oxygen with Fraction of Inspired Oxygen. Vasopressin and Adrenaline was used only in one patient each.

HR: Heart Rate; MAP: Mean Arterial Pressure; CVP: Central Venous Pressure; SVRI: Systemic Vascular Resistance Index; GEDI: Global End Diastolic Index; CI: Cardiac Index; PPV: Pulse Pressure Variation; SVV: Stroke Volume Variation; PVI: Pleth Variability Index; ScvO2, central venous oxygen saturation.

HR: Heart Rate; MAP: Mean Arterial Pressure; CVP: Central Venous Pressure; SVRI: Systemic Vascular Resistance Index; GEDI: Global End Diastolic Index; CI: Cardiac Index; PPV: Pulse Pressure Variation; SVV: Stroke Volume Variation; PVI: Pleth Variability Index; ScvO2, central venous oxygen saturation

HR: Heart Rate; MAP: Mean Arterial Pressure; CVP: Central Venous Pressure; SVRI: Systemic Vascular Resistance Index; GEDI: Global End Diastolic Index; CI: Cardiac Index; PPV: Pulse Pressure Variation; SVV: Stroke Volume Variation; PVI: Pleth Variability Index; ScvO2, central venous oxygen saturation.

AUC: Area Under the Curve; SE: Standard Error; CI: Confidence Interval; CVP: Central Venous Pressure; SVV: Stroke Volume Variation; PPV: Pulse Pressure Variation; PVI: Pleth Variability Index;  GEDI: Global End Diastolic Index.

Discussion

This study aimed to compare the ability of PVI with the more established parameters PPV, SVV, and GEDI to predict fluid responsiveness in mechanically ventilated patients with severe sepsis or septic shock. The main finding is that none of the above haemodynamic parameters were able to reliably predict fluid responsiveness despite exclusion of common known confounding factors. We observed a significant number of false positive and false negative results considering previously cited cut-off values for dynamic parameters in general ICU and more specifically in ventilated septic patients [4,5,8-10]. Our study population consisted of ventilated patients with severe sepsis and septic shock. All but three patients were receiving vasopressor support. Known confounding variables affecting the ability of dynamic parameters to predict fluid responsiveness were excluded: all patients were in sinus rhythm during the study period and did not have any arrhythmia; all were deeply sedated without any spontaneous breathing activity and received a tidal volume of 8ml/kg estimated lean body weight. Haemodynamic measurements were performed using the PiCCO 2 monitor which is a well validated accurate monitor measuring SV even in rapidly changing circulatory conditions [11] and in patients with reduced cardiac function [9]. At least three cold boluses were given randomly throughout the respiratory cycle using the same sampling period (30 seconds) to obtain relevant haemodynamic data using transpulmonary thermodilution [12]. In line with other studies, we used a fluid bolus of 500ml Gelofusine® administered over 30min [5]. The mean CVP increased after volume expansion in both responders and non-responders by at least 2mmHg (Table 3 & 4), which has been defined previously as a proof for an adequate fluid challenge [13]. We explored the possible reasons for the unexpected finding that none of the dynamic parameters reliably predicted fluid responsiveness in our study. Less than 50% of our patients were responders. This is not uncommon in critically ill patients with severe sepsis/septic shock or after cardiac surgery [10,14,15]. It is known that septic shock is frequently associated with biventricular dysfunction and increased pulmonary artery pressure [16]. Both RV and LV failure are well known confounders altering the magnitude and ability of PPV and SVV to predict fluid responsiveness [17]. Impaired RV function is also a frequent problem in ARDS, a condition commonly associated with septic shock [18]. In case of RV dysfunction/failure, one might observe "false" high PPV and SVV in non-responders as the RV after load, in contrast to preload change, is the major determinant for high PPV and SVV [14,19]. This could be further exacerbated by increased pulmonary artery pressure, large tidal volumes and high PEEP [18,20], the latter two of which were present in our study (Table 1). Previous studies on the ability of dynamic parameters to predict fluid responsiveness in septic patients either did not measure pulmonary artery pressure [5], pulmonary artery pressure was not significantly raised [3] or PEEP values were low [10]. In our study, all but three patients received vasopressors, which can independently increase pulmonary artery pressure. Daudel and colleagues demonstrated that, in contrast to haemorrhagic shock, in endotoxemic shock with raised pulmonary artery pressure, PPV did not predict fluid responsiveness [19]. A similar conclusion was reached by VanBallmoos who reported a reduced RV ejection fraction in almost half the non-responders and in none of the responders in patients with septic shock or post cardiac surgery [14].

In case of LV dysfunction/failure both PPV and SVV are generally decreased [3,17]. However, Mesquida et al have shown that if PPV and SVV are being used for fluid resuscitation in heart failure conditions, the phase relation between airway pressure and the maximal SV and hence PP needs to be  determined [17]. If the LV is afterload dependent, one could observe a simultaneous increase in SV and hence PP when intrathoracic pressure increases and thus PPV and SVV might be high without reflecting fluid responsiveness particularly if the tidal volume is high and/or the chest wall is stiff e.g. due to sepsis induced oedema. For the haemodynamic measurements taken by the PiCCO system the phase relation between the change in airway pressure and maximal PP and SV is unknown. PPV and SVV are calculated over a 30sec rolling period. Reuter et al reported that SVV measured by the PiCCO system is still a reliable marker of fluid responsiveness in LVF with EF<35% [9]. However, in this study the AUC for SVV to predict fluid responsiveness in patients with impaired LV function was 0.76 which was lower than the AUC for SVV to predict fluid responsiveness in a second group of patients with normal LV function (0.88).

Gruenewald et al reported that in animals suffering from stunned myocardium shortly after cardiac arrest all dynamic parameters are unreliable in predicting fluid responsiveness [21]. Wiesenack and colleagues, found no correlation between SVV measured by the PiCCO system and prediction of fluid responsiveness in patients undergoing elective coronary artery bypass surgery, with an ejection fraction >50% [22]. In this study the authors speculated that arterial pulse contour- derived estimates of SVV are potentially unreliable under positive pressure ventilation. PPV is considered the more sensitive and specific parameter compared to SVV in predicting fluid responsiveness as pressure measurements are usually more accurate than SV measurements. However, in our study neither baseline SVV nor PPV could reliable predict fluid responsiveness. SV and PP are tightly correlated during positive pressure ventilation [17]. The magnitude of PP for any given SV depends on central arterial compliance. Thus, a vasopressor induced reduction in central arterial compliance could lead to large changes in PP and hence PPV even for small changes in SV. The majority of the patients in our study were treated with vasopressors and it is tempting to speculate that this might be a further explanation why some patients were unresponsive to fluids despite high baseline PPV. Furthermore, it is conceivable that a more pronounced inspiratory increase in PP is due to an exaggerated dUp phenomenon in the presence of reduced LV function [8]. which might have contributed to an increase in PPV in non-responders.

As the cyclic changes in RV and LV pre- and after load are dependent on cyclic changes in intraalveolar, intrapleural and hence transpulmonary pressure any factor affecting one or a combination of these would have an impact on all dynamic parameters. Increasing tidal volume directly increases the magnitude for PPV and SVV for any given chest and lung compliance [17]. Intraabdominal pressure affects chest wall compliance and hence intrapleural pressure. In fact, Jacques et al showed that the cut-off values for all dynamic parameters increase significantly if intraabdominal pressure is increased [23]. We did not measure intra abdominal or intrapleural pressure in our study. Respiratory system compliance was not significantly different in both groups. However, we cannot exclude the possibility that differences in transpulmonary pressures induced by the same tidal volumes might have contributed to our findings. Loupec et al showed that PVI reliably predicts fluid responsiveness in critically ill ventilated patients [4]. However, this result has not always been replicated in septic patients treated with vasopressors [10,15,24]. One possible explanation for this finding could be that the proportion of septic shock patients was lower in Loupec's study (55%) than in the other studies (85%, 86%) [4,10,15].

Conclusion

We conclude that the dynamic parameters PPV, SVV and PVI may not be able to predict fluid responsiveness in all ventilated patients with severe sepsis or septic shock even after exclusion of already commonly known confounding factors. An assessment of RV and LV function and measurement of intraabdominal or even transpulmonary pressure should be taken into account before interpreting and acting on the values measured. Passive leg raising, as a "reversible” fluid challenge might help to prevent unnecessary and potential harmful fluid loading provided intraabdominal pressure is not increased [25].

Acknowledgement

Hardware and software for the conduct of the study were supplied by Masimo Corp., Irvine, CA, USA.

The study was supported by a grant from the Research Development Department, The James Cook University Hospital, Middlesbrough, United Kingdom.

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Supraorbital/Supratrochlear Nerve blocks: Clinical Significance of the Superior and Anterior Approaches-Juniper Publishers

Introduction

Hair restoration is one of the commonest cosmetic surgery procedure in men [1]. The procedure is performed under local anaesthesia. Many of the patients are anxious about the degree of pain to be expected during and after the surgery. The pain of the local anaesthetic agent is dependent on various factors like needle gauge, composition, temperature, pH, speed of injection, anatomical structure/area etc. Various maneuvers are used to decrease the pain during the administration of local anaesthesia like vibration anaesthesia Cryotherapy etc [2-4]. With the introduction of newer drugs for local anaesthesia, the safety is increased.

Peripheral nerve blocks constitute a major tool in the armamentarium in the office-based cosmetic surgery procedures. Supraorbital (SO) and supratrochlear (ST) nerve are the terminal branches of the frontal nerve [5]. These nerves supply mainly the skin of the forehead. These nerve blocks are beneficial in many procedures. The SO/ST nerve block during hair transplant surgery decreases the severity of the pain for recipient site injections. Their blockage is beneficial in treating disorders like trigeminal neuralgia, migraine etc [6,7]. These nerve blocks also result in significant decrease in the need of additional analgesics and opioids [8]. The SO/ST nerves collectively provide sensory innervation to the forehead and frontal scalp as well as to the vertex (Figure 1). The anatomical details and variations of these nerves is very essential for a proper anaesthesia.

The supraorbital (SO) nerve emerges from the supraorbital foramen or notch. The foramen or notch is located about 27 mm lateral to the glabellar midline. However, the distance varies if different races [9,10]. The nerve divides into medial and lateral branches. Similarly supratrochlear (ST) nerve emerges through supraorbital notch about 17mm from glabellar midline. It follows one of the four courses i.e., Ia (ST nerve emerges independently from SO nerve as a single nerve through Corrugator Supercilli muscle), Ib (ST emerges independently from SO nerve and bifurcates into 2 branches prior to entering the Corrugator Supercilli muscle), IIa (ST nerve emerges from SO notch with SO nerve and passes through Corrugator Supercillimuscle as a single nerve), and IIb (ST emerges from SO notch with SO nerve and bifurcates into 2 branches prior to entering the Corrugator Supercillimuscle) [11].

There are two techniques to accomplish SO/ST nerve block, i.e., anterior and superior. In superior approach, the needle is inserted from the cephalic side in such a way that the tip of the needle is felt at SO foramen by the palpating finger of the physician's other hand. Whereas in the anterior approach, the physician stands on the side of the patient and the needle is directed towards the midline. The following study was undertaken to compare the pain levels of anterior and superior approaches.

Materials and Methods

The study was conducted in 30 patients undergoing SO/ST nerve clock for hair restoration surgery. The patients undergoing 1st session were included. The informed consent was taken. All the injections were administered by the surgeon. A 3ml syringe with 30 oG needle was used containing 1% Xylocaine with adrenaline is 1;100,000 dilution. Separate needle was used for each side.

Superior Approach

The needle was introduced about 2cm above the SO foramen palpated. About 0.5ml of the anaesthetic solution was injected. The needle was advanced caudally till the tip was felt at the foramen and 0.5ml was injected here. The needle was withdrawn slightly and directed laterally injecting about 1.0ml in a 'fanning out' way. The needle was again withdrawn and directed medially injecting about 1.0ml. This technique encompassed all the possible branches of the SO/ST nerves (Figure 2).

Anterior Approach

The SO foramen was palpated and the needle was inserted from the front side of the patient. Care was taken not to puncture the SO nerve. About 1.0ml was injected here. The needle was withdrawn and 1.0ml was injected on medical and 1.0ml on lateral side (Figure 3). At the end of the procedure, the patients were asked to rate the pain according to the Wong Baker Faces Pain Scale [12] (Figure 4). The patients were also asked to give their feedback on the choice of technique for the next time. The data was analyzed statistically by Mann-Whitney's U-test (using the Easy Statistics Calculator©, version 1.2.0, Saitama, Japan, copyright 2016).

Results

A total of 35 patients were included in the study. The mean age was 33.4 years (range; 18 to 56). The mean pain score was 4.14 in anterior approach whereas 2.85 in superior approach (Table 1). About 31.4% of the patients were smokers. The pain score in smokers vs non-smokers was 4.09 vs 2.82 in anterior approach respectively. Where as in superior approach, the mean score was 4.27 vs 2.86 in smokers and non-smokers respectively. About 20% patients were anxious about the anterior approach that the needle may hit the eyeball. About 71.4% of the patients voted for superior approach on both sides for the next time.

Discussion

The role of SO/ST nerve block is well established in plastic surgery. It is routinely performed for the management of different kinds of headaches like tension headache, chronic headaches, migraine etc [6,7]. It is also the mainstay of regional anaesthesia in office-based cosmetic surgery procedures like hair restoration procedure [13]. To carry out a successful SO/ ST nerve block, the relevant anatomy is  of utmost importance which helps to locate the nerves and block them.

The sensory innervation of the face is supplied by trigeminal nerve which has five branches4. The frontal nerve enters the orbit via superior orbital fissure and passes anteriorly beneath the periosteum of roof of the orbit. The frontal nerve gives off a larger lateral branch, the supraorbital nerve, and a smaller medial, supratrochlear nerve. The SO nerve exits the SO foramen or notch along the superior rim of orbit, accompanied by the artery and vein. In the notch or foramen, SO nerve gives off branches which supply mucosal membrane of frontal sinus and filaments which supply upper eyelid. Above the rim, SO nerve divides into superficial and deep branches.

The medical (superficial) branch passes over the frontalis muscle and divides into multiple smaller branches with cephalic distribution towards the hairline. It provides sensory innervation to the forehead skin and anterior scalp as far as the vertex. The deep branch (laterla0 runs deep in the frontalis across lateral forehead between galeaapo neuroticanad pericranium. It provides sensory innervation to underlying periosteum and frontal parietal scalp. The ST nerve is the branch of the frontal nerve and supplies sensory innervation to the bridge of the nose, medical part of upper eyelid and medial forehead. Usually ST nerve is located about 17mm from midline and SO nerve at 27 mm from midline.

The two approaches for SO/ST nerve block are well- established. The current study is first of its kind to compare the differences in terms of pain and patients' anxiety. The superior approach was found to be clinically/statistically significant (p<0.5). There are many factors which influence the experience of pain perceived by patient but the technique of SO/ST nerve block remained one of the significant factors. The visualization of watching the injection near the eyeball probably resulted in high level of anxiety in anterior approach.

The study by Chang et al described the pain of SO/ST nerve block to be between 1 and 2 (out of 10) whereas in the present study, the average pain score was 4.4 (out of 10) [14]. In another study, the average pain score was 3.9 (out of 10) and 6.8 9 out of 10) in SO/ST nerve block with and without the use of topical anaesthetic cream [15]. In another study, the mean score also remained 3.86 [16]. In these two studies, the anterior approach was used for administering SO/ST nerve block. In the present study, the pain score was found to be doubled in anterior approach as compared to the superior approach. The pain of superior approach remained 2.85.

Distraction during the administration of local anaesthesia injection plays a very important role [4,17].  In the present study, all the injections were administered by the surgeon. The needle gauge, room temperature and environment were kept the same in all the patients. The speed of the injection was kept slow and maintained by the surgeon to a very slow in all the patients. The Wong Baker Faces pain scale was used for rating as the scale gives the opportunity to the patients to express how they feel as it has a well established reliability and validity even in children [18,19].

Conclusion

The superior approach for administration of supraorbital/ supratrochlear nerve block proved to be better approach as far as the patient's anxiety about the injections is concerned. It also proved to be less painful.

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Radiation-Induced Vasculopathy-Juniper Publishers

Introduction

A 54 year-old man had several months of near-syncope and global weakness occurring typically with walking that worsened after starting antihypertensive medications including a diuretic. He had been treated for Hodgkin's lymphoma, presenting as a nasal mass as a young adult, with chemotherapy and external beam radiation. He had a normal head CT and felt somewhat better after receiving intravenous fluids but his symptoms returned on ambulation. MRI and MRA (Figure 1) of his head and neck showed occlusion of his left common carotid artery, highgrade stenosis (>75%) of his right internal carotid artery, and severe disease of both vertebral arteries; MRI showed numerous scattered punctate infarctions We started a Heparin infusion, held all antihypertensive medications allowing for permissive hypertension, and consulted Vascular Surgery for urgent right carotid endarterectomy. His recovery was complicated by postoperative infection but he had no further neurological symptoms at his three month follow-up visit.

Radiation-induced vasculopathy may take years to decades to become clinically symptomatic. Diuretics and vasodilators may worsen cerebral perfusion and exacerbate symptoms potentially leading to stroke [1-5].

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The Conversion from Continuous Sufentanil Infusion to Oral Retarded Opioid Medication: Beware of the Equi-Analgesic Opioid Ratios - A Case Series-Juniper Publishers

Abstract

Background: Sufentanil has an outstanding place in clinical practice and one cannot think of surgery or intensive care therapy without it. However, the routine use of continuous sufentanil infusion may cause severe problems if stabilized patients are discharged from the ICU after surgical treatment and need to be converted to oral opioids.

Aim & method: Here we report our experiences with a series of six patients that we have converted from intravenous sufentanil to oral morphine.

Cases: In 6 cases, we report intensive care (ICU) patients after surgical or medical therapy, who received sufentanil infusion for analgosedation. The patients were between 45 and 68 years old. It can be demonstrated that the optimal dose of sufentanil can be converted to minor doses of oral medication than expected from the calculated equi-analgesic ratios. Despite of lower oral opioid medication pain levels did not increase after conversion.

Conclusion: We recommend to begin opioid conversion with 10% of the calculated equivalent dose of intravenous sufentanil when converting to oral long-acting morphine and afterwards to further adapt the dosage.

Introduction

Since its development in the late 70s, sufentanil has an outstanding importance in clinical practice and one cannot think of surgery or intensive care routines without this treatment. The substance delivers a much higher potency than its parent drug fentanyl with an expanded therapeutic range [1,2]. From the beginning of its clinical use, sufentanil was the intravenous opioid of choice for hemodynamically instable patients [3]. Due to its outstanding hemodynamic stability resulting from a minor impact on cardiac index, left ventricular ejection fraction and heart rate [4], sufentanil is broadly used for critically ill patients in cardiac and non-cardiac surgery. In comparison with fentanyl, it has a shorter context-sensitive half time that results in better controllability [5] and predisposes the use of sufentanil in extended cases and for continuous infusion in intensive care.

The decoupling of analgesia and respiratory depression [6] is another reason for preferring sufentanil during weaning of mechanically ventilated patients or in those with spontaneous breathing. However, the routine use of continuous sufentanil analgosedation in the ICU may result in the problem that stabilized patients are still not free of pain or suffer from chronic pain and thus need to be converted to oral opioid medication, if discharged from the ICU after surgical or medical therapy. For example, common dosage of 20μg of sufentanil per hour has to be substituted by oral opioids as the patient should be transferred to the floor. The calculated equivalent dose for oral substitution would be 1440mg morphine per day, which is, of course, not practicable.

The following cases should demonstrate that sufficient pain therapy can be achieved also with significantly lower morphine doses. We report here six cases in which the hospital pain service was consulted to assist non-anesthetic intensive care units in the conversion from intravenous sufentanil to oral medication.

Case Presentation

Case 1: Patient J.S., male, 44 years old, weight 170kg, height 175cm; septic shock with multi-organ failure

The patient who suffered from arterial hypertension, atrial fibrillation, type-II-diabetes mellitus and morbid adipositas was admitted due to severe and rapid deterioration of his general condition. He developed a septic shock with subsequent multiorgan failure including renal insufficiency requiring dialysis, and liver failure. Furthermore, he developed a cardiogenic shock with a left ventricular ejection fraction of about 10%, and required cardio-pulmonary resuscitation (CPR) as ventricular fibrillation occurred.

After improvement and when the patient was able to be transferred to the floor, he received sufentanil infusion with 25μg per hour. The patient reported pain scores between NAS four and eight with burning quality. Pain therapy was converted orally to long-acting morphine (MST®, Mundipharma Ltd., Limburg an der Lahn, Germany) 3x100mg and 30mg mirtazapine (REMERGILSolTab®, MSD Sharp & Dohme GmbH, Haar, Germany) in the evening and short-acting morphine(Sevredol®, Mundipharma Ltd., Limburg an der Lahn, Germany), 20mg up to six times daily on demand. After a stepwise reduction of the morphine dose down to 3x30mg long-acting morphine per day and 30mg of mirtazapine, the pain service could sign off after seven days.

Case 2: Patient P.M., male, 63 years old, weight 97kg, height 180cm; serial rib fractures with pleural empyema

*This patient received additionally transdermal fentanyl (Durogesic SMAT 75pg/h)

The patient suffered from a traumatic left-sided rib series fracture and developed pneumonia and a pleural empyema while under conservative therapy. Secondary diagnoses comprised arterial hypertension, COPD, type-II-diabetes mellitus and chronic renal insufficiency. After surgical intervention and intensive care therapy with prolonged weaning, the patient was presented to the pain service for conversion to oral opioids. The current pain therapy was 20μg/h of i.v. sufentanil (Table 1). The patient was switched to 3x60mg long-acting morphine sulphate (MST®, Mundipharma Ltd., Limburg an der Lahn, Germany) and 15mg mirtazapine (REMERGIL SolTab®, MSD Sharp & Dohme, Haar, Germany) in the evenings; additionally Sevredol® 20mg up to eight times daily was prescribed, if VAS exceeded 5. After a stepwise reduction of the morphine dose down to 3x30mg with an evening dose of 15mg mirtazapine, pain service consultation ended after four days, the patient being satisfied at VAS <4.

Case 3: Patient S.L., female, 53 years old, weight 146kg, height 170cm; sepsis with multiple arterial emboli

The patient was primarily treated for a sepsis with unknown focus and suffered from morbid adipositas, a history of hypertension and type-II-diabetes mellitus in the intensive care unit. During the clinical course, both legs had to be partially amputated due to multiple arterial emboli; the right leg below the knee, the left leg above.

Under sufentanil infusion of 40μg/h, the patient was presented for conversion to oral therapy. The initial regime comprised 3x100mg of long-acting morphine with pregabaline (Lyrica®, Pfizer®, Berlin, Germany), 2x150mg, and Sevredol®, 20mg up to 6 times daily, if VAS exceeded 5. The consultation ended after five days, with morphine dosage reduced to 3x30mg of long-acting morphine and pregabaline 2x150mg. The patient was satisfied at VAS <3.

Case 4: Patient K.K., male, 58 years old, weight 104kg, height 180cm; osteomyelitis and acute renal failure after coronary arterial bypass grafting (CABG) surgery

The patient was treated for sternal osteomyelitis and acute renal failure after coronary arterial bypass grafting. In addition, the patient suffered from arterial hypertension, peripheral arterial vascular disease, hyperlipoproteinemia, COPD (GOLD III) and had been treated previously for laryngeal cancer with laryngectomy and bilateral neck dissection. At presentation to the pain service for conversion to oral medication, the patient received 20μg/h sufentanil with additional transdermal fentanyl (Durogesic SMAT 75μg/h, JANSSEN-CILAG, Neuss, Germany), which the patient had already before surgery. Pain scores of VAS=6 with peaks at VAS=8 were reported. The patient was converted to long-acting morphine 3x100mg/day and additionally with 3x100mg carbamazepine (Carbamazepin HEXAL®, Salutas Pharma, Barleben, Germany) with opportunity of receiving supplementary 20mg Sevredol®, up to 8* per day. After reducing long-acting morphine to 2*50mg with carbamazepine 3*300mg, pain service consultation ended after six days, the patient being satisfied at VAS=3-4.

Case 5: Patient R.S., male, 66 years old, weight 80kg, height 178cm; Multiple Myeloma and ARDS

The patient needed mechanical ventilation support for acute respiratory insufficiency under pre-existing multiple myeloma. During the clinical course, the patient developed acute renal failure requiring dialysis, aspiration pneumonia and critical illness polyneuropathy. After prolonged weaning, an apparently pain stricken patient was presented to the pain service receiving 20μg/h sufentanil, for conversion to oral analgesics.

At pain levels of VAS=5 and peaks of VAS=9, initially long- acting morphine 3*100mg/day with 150mg pregabaline (Lyrica®, Pfizer, Berlin, Germany) in the evenings was prescribed, with the possibility of additionally receiving 8*20mg Sevredol® per day. After stepwise reduction of morphine dose to 2*20mg/d of long-acting morphine and 150mg pregabaline in the evenings, the patient was discharged from the ICU with VAS=3 and the patient was discharged with 2*10mg/d long- acting morphine and with 150mg pregabaline.

Case 6: Patient K.B., male, 62 years old, weight 60kg, height 160cm; hemorrhagic shock after bypass surgery of the femoral artery

Following bypass surgery of the femoral artery with secondary hemorrhage and hype volemic shock, the patient developed an urosepsis. Preexisting diagnoses were peripheral vascular disease, arterial hypertension, type-2-diabetes mellitus and stage-III-renal insufficiency. After stabilizing the patient and planning for discharge to the ward, pain service was consulted for conversion of i.v. Sufentanil, 20μg/h, to oral medication.

The patient described pain as having piercing/stabbing qualities at VAS=3, peaking at VAS=9. After a stepwise reduction of initially 3*100mg/day long-acting morphine with mirtazapine 15mg for the night, the patient was discharged from the ICU with 3*60 mg/d long-acting morphine with afore mentioned mirtazapine at VAS=1.

Discussion

In clinical practice, sufentanil is indispensable for anesthesia and intensive care therapy. However, a conversion from continuous sufentanil infusion to oral opioid medication is essential for discharge from the ICU; however, current literature offers no usable conversion algorithms.

The pain levels of a series of six patients presented here indicate that opioid conversion to lower oral doses does not result in an increase of pain scores. Additionally administered psychotropic drugs may also have an effect on alleviating pain, yet two aspects have to be taken into account: (1) pain aggravation by under-dosing of opioids cannot be compensated by psychotropic medication, and (2) if the opioid dose is titrated to an optimum, psychotropic drugs cannot further reduce this dose. They can only be used to avoid severe side effects of opioid therapy [7]. In the present cases, psychotropic medication was used to treat effects of opioid over-dosing after conventional conversion, and was needed to treat the neuropathic aspects of the respective pain qualities [8].

It is important to note that the conversion to oral opioids is not an "opioid rotation", although one has to calculate an equi- analgetic dose. The concept of opioid rotation addresses the problem of excessive side effects [9] of a single opioid or the insufficient effect on pain [9,10]. This was not the case in the presented patients. In those, we intended to switch an i.v. opioid to an orally applied one, much in the way a morphine drip is switched to oral retarded morphine.

Sufentanil is available as a non-i.v. preparation for sublingual, buccal and nasal administration but not in a long- acting formulation. As the application route switch is usually for a single compound and the long-acting formulation is commercially unavailable, change to long-acting morphine was necessary, but not in the sense of an opioid rotation.

In current references, only the general recommendation to begin oral substitution with approximately 50% of the equivalent dose can be found [10,11]. These recommendations are based on the thought that on one hand the patients have not benefitted from the current opioid and on the other they offer concomitant clinical limitations (i.e. advanced age, renal damage, cardiopulmonary insufficiency, etc.) that makes a 1:1 switch to a new opioid inappropriate.

The patients in the presented cases had an i.v. sufentanil medication near the optimum dose. The available conversion tables and factors suggested a 900% higher dosing than that we eventually applied. Even with a reduction of 50% from the given i.v. dose, the orally administered amount would still have been in excess of 350% of the dose that is finally necessary. This is striking, as inadequately high doses of opioids can lead to severe side effects such as attention deficits, optical hallucinations and ultimately respiratory depression [12,13].

From the present data, we provide evidence that, when converting i.v. sufentanil to oral morphine, a much steeper reduction of the equivalent dose is urgently warranted.

We would like to recommend starting with 10-20% of the calculated equivalent dose of sufentanil infusion when converting to oral long-acting morphine and afterwards adapting the morphine dosage further. Possible co-medication with neuroleptics and benzodiazepines should not be ignored in order to further minimize opioid doses and to decrease severe side effects.

In the possible case that the conversion to a long-acting opioid proves insufficient, a similar approach as usually followed in opioid conversion should be used: In addition to the estimated dose, rescue medication needs to be provided. This can be claimed every hour by the patient and, in the case of using morphine sulfate, doses of 10mg and 20mg with an onset of 15 to 20 minutes should be available. It seems important that none of our patients claimed rescue medication.

Conclusion

Owing to safety considerations, we propose to approach the final opioid dose from a lower dose. By doing this, severe side effects and a possible readmission to the intensive care unit can be avoided. Moreover, since the increased pain perception precedes withdrawal symptoms, correcting the opioid dose in an hourly interval would not have led to withdrawal indicators [14-18].

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Smart I Pill Dispenser-Juniper Publishers

News

The economic burden of the opioid epidemic cost the US $78.5 billion a year. A person dies from an opioid overdose every 20 minutes which totaled 30,091 people last year. It is an epidemic that difficult to treat. Opioid overdoses now outnumber the number of deaths from gun violence and motor vehicle accidents per year. Over 90% of patients who overdose on prescription painkillers are prescribed opioids again. Currently in the US there are 100 million people in chronic pain who are dependent on prescription opioids, 1 million veterans from war who are dependent on prescription opioids, 20 million who abuse prescription opioids and there is 30,000 who die from prescription overdoses.

Opioids are necessary to treat pain but the prescription opioid overdose has become a significant national problem. Life expectancy in the US has dropped to 73 years and 8 months largely because of it. The opioid epidemic was rooted by a US government agency JCAHO (Joint Commission on Accreditation of Healthcare Organizations now referred to as the Joint Commission) policy in 2001 that declared pain as the 5th vital sign which has now lead to make prescription opioid abuse/ addiction and the respiratory depression leading to death a complex problem primarily in US. 90% of the opioids consumed in the world are consumed in the United States. JCAHO began an education of the public and of the medical community that patients deserved to be pain free. Opioids were deemed safe to prescribe and deemed to have a low addiction potential. Hydrocodone was prescribed rather freely and the introduction of OxyContin compounded the growing problem. Treatment of Opioid abuse/ addiction and the respiratory depression leading to death is a complex problem to solve. 90% of those who overdose on prescription opioid pain medications are returned back on opioids by their physicians. 80% of the prescription opioids responsible for an overdose come from friends or family. Naloxone and Suboxone, two drugs touted as the solution to the opioid epidemic, unfortunately represents an afterthought. Naloxone an opioid antidote is designed to treat patients already actually overdosed on opioids and Suboxone is designed to treat patients already addicted on opioids. It is a little too late to be effective. In fact, studies report that 90% of patients who overdose on opioids do not get Naloxone or Suboxone. When realization by government agencies that chronic opioids could cause addiction and abuse it was too late. The whole country was basically taking opioids. In 2014 there were 261 million opioids prescribed for a US population of 319 million people. Every single adult in the US could have received a prescription for a bottle of opioids. The governmental policy to the opioid overdose crises was to limit access to opioids with REMS (Risk Evaluation and Mitigation Strategies) and CURES (Controlled Substance Utilization Review Evaluation System). Unfortunately, the policy to limit opioid access it has significantly worsened the problem and has created another problem. The opioid overdose death rate in the US quadrupled in the last 10 years and addicts desperate to recycle their euphoria with access to prescription opioids limited were forced to resort to the cheaper and easily accessible alternatives namely Heroin. The Heroin addiction in the US has quadruple in the last 10 years. Heroin is has become even more deadly because it is now being «cut» with fentanyl and the even more deadly counterpart, car-fentanyl which are at least 100 times more potent than Morphine.

There is no solution to prevent overdoses and allow safe treatment of pain. There are tamper proof opioids, extended release opioids, and abuse deterrent formulations of opioids on the market now to prevent overdoses. There is unfortunately no pivotal evidence to support their to use. All these tamper proof, extended release, and abuse deterrent formulation manipulations of opioids have one weakness - ingestion. The oral route is most common method of administration of opioids and it is the simplest method in which to abuse opioids. It is easy to ingest more drug than prescribed. Doctors prescribe opioid pills. Pharmacists fill opioid prescriptions. But when these patient obtain a bottle of pills from the pharmacy, there is nothing to prevent the patient from taking one pill or ten pills or the whole bottle of pills. To treat a opioid addict with more opioids is intuitively illogical because the opioid addiction is not treated. It is tantamount to treating an alcoholic with more alcohol without treating the alcoholism. It is a disease that requires more than just a special type of pill. Rather than focusing just on the treatment of pain perhaps the focus should be on the treatment of the patient as whole.

The solution to the opioid epidemic could possibly involve ensuring compliance of of patient to the opioid prescription directions. Patients who are dependent, abuse, and addicted to opioids are different from other patients in terms of their level of compliance. These want to take their opioids, and they will never forget to take them. If they run out supply, they frequently attempt to get more prescription opioids from family members or friends who have an extra or an unused amount before going to illicit sources. Tamperproof, extended release and abuse deterrent formulation used as preventive measures may be employed but it must be understood that patients still overdose and die with these manipulations because of the simple method in which they can be abused. We know this information is likely correct because the death rate from prescription opioids has quadrupled since 2004 and still continues to climb even in their presence. Severely limiting or curtailing opioids amounts to ineffective treatment of pain and encourages patients to progress to Heroin to seek relief. This information suggest that perhaps the treatment paradigm needs to be altered by controlling the physical oral procedure of ingesting these drugs. This can be done with a smart pill dispenser that is biometric fingerprint controlled. The smart pill dispenser would enhance compliance to the prescription by dispensing of pills only as prescribed. The number of pills and the time interval between pills would be controlled preventing an overdose. The biometric fingerprint controller would ensure that only the patient would be able operate the device to dispense the opioid and would also serve to prevent sharing. The patients would receive their prescription opioid for treatment for their pain and forced into compliance by the smart pill dispenser that would prevent over ingestion of the opioid leading to an overdose. The patient would be alive to seek proper treatment of their addiction whether it would be a comorbid medical issue, psychosocial issue or a socioeconomic issue.

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Thoughts on Pain Management, Postoperative Nausea and Vomiting (PONV) & Brain Fog-Juniper Publishers

Introduction

Persistent anesthesia problems may be summarized as over- and under-medication, pain management, and postoperative nausea and vomiting (PONV).

Over- &Under-Medication

Prior to the 1996 FDA approval of a direct cortical responsemonitor (DCRM), determination of anesthetic dose relied on body weight, medical & physical assessment (i.e. ASA status), and heart rate (HR) and blood pressure (BP) changes, especially thesevital signs changes occurring with initial incision.

The cerebral cortexis the target of anesthetics. The adult brain weighs approximately 3-4 pounds and doesn't vary substantially with body weight.Average body weight doses based on the '70 kg' patient will likely over or under-medicate many patients. ASA status is also an unlikely guide to individual cortical responses to body weight based drug doses.

Pharmacokinetics (PK) and pharmacodynamics (PD) as well as target controlled infusion (TCI) are alternative, yet indirect, measures of cortical response by way of predicting anesthetic blood levels. These approaches would be acceptable if blood levels, not the cortex, were the anesthetics' target.

Vital signs (i.e. HR and BP) are brain stem functions. The American Society of Anesthesiologists’ (ASA) awareness with recall study showed that half of patients who experienced awareness had no change in either HR or BP with which to alert their anesthesiologist [1]. This finding was not an especially surprising since consciousness, memory and pain perception are cortical, not brain stem, functions.

Under-medication is estimated to occur in only 0.1% of patients and may result in PTSD in them. Unpleasant an experience as awareness with recall can be, there are no documented cases of death from anesthesia awareness. Many of the remaining 99.9% of patients may be subjected to routine over-medication ( Figure 1).

Not only does one American patient every day perish (mortality) from anesthesia over-medication but also 16M of the 40M patients (40%) every year emerge with 'brain fog' (morbidity) [2]. Brain fog may be defined as delayed anesthetic emergence, but also can include postoperative cognitive dysfunction (POCD) or even delirium [3-5].

Postop brain fog creates additional morbidity while adding substantial additional costs to the health care system caring for patients who cannot be quickly processed and discharged from the system. Additionally, patients must endure the long-term consequences of their anesthesiologists’ short term care.

The DCRM has been validated in over 3,500 published studies and can be found in 75% of US hospitals. The question remains 'why is directly measuring the organ being medicated with a DCRM monitor only routinely done 25% of the time?’

Part of the answer may lie in the manner in this monitor was originally configured. On a unit-less scale of 0-100, the lower the number, the more sedated the patient. This number is a derived, not directly measured, value. The 15-30-second delay from real time places the anesthesiologist in the unfavorable position of catching up to patient needs instead of being able to anticipate them. This creates a situation like trying to drive one's car with only the rearview mirror's information, not especially safe or useful ( Figure 2).

The first anesthesia textbook with a DCRM monitor on its cover also displayed the electromyogram (EMG) of the frontalis muscle (akin to the EKG of the cardiac muscle) in the picture ( Figure 3). The text described the utility of this real-time signal; i.e. EMG spikes signal incipient arousal and the need to proactively increase sedation to return the EMG to baseline [6]. All that is needed to display the EMG is to use the existing software to select and save it as the secondary trend.

Most patients achieve propofol sedation adequate enough to prevent awareness and recall at 60<BIS<75 (with baseline EMG) level of with 25-50 mcg-1 .kg'1 .min. Over 18-years’ experience titrating propofol with DCRM, variation of as little as 2.5 mcg-1 .kg-1 .min and as much as 200mcg-1 .kg-1 .min has been observed to achieve the same level of amnesia and sedation. ‘Apples’ to ‘apples’ comparisons between patients, despite the nearly hundred-fold observed variation in propofol requirements to achieve, become more meaningful when using numerically based definitions of levels of consciousness achieved [7].

Postoperative brain fog likely is a multi-factorial problem. Until universal DCRM monitoring becomes a standard of care, it will not be possible to clarify the role routine over-medication plays [8]. It is unlikely beneficial for elderly patients to routinely administer 30% more than what is needed to achieve 60<BIS75. Common sense is uncommon ( Figure 4) - Voltaire.

Pain Management

Most people know it does no good to close the barn door after the horses have escaped. But too many anesthesiologists still need to be convinced that it’s futile to try to prevent postop pain by allowing surgeons to cut without first blocking the midbrain N-methyl, D-aspartate (NMDA) receptors [9,10].

Local anesthetic skin injection or incision is an extremely potent signal to the brain that the "world of danger" has invaded the "protected world of self." The sedated brain can’t differentiate between the mugger’s knife and the surgeon’s scalpel (or trocar). While there are certainly other internal pain receptors, no signal is more determinant of post-operative pain than of skin incision (or skin injection). An unprotected incision sets off the major cortical alarmsthat initiate the wind-up phenomenon.

Surgery is a painful experience.Most anesthesiologistsbelieve acardinal function is the prevention of pain during surgery. From 1975 through 1993, this author had never once considered why there was a need for postop opioid rescue for many, if not most, patients. In 1992, a clinical trial began using 50 mg IV ketamine, 2-3 minutes prior to stimulation AFTER propofol hypnosis to dissociate patients for pre-incisional local anesthesia injection [11,12].

When propofol is incrementally titrated ketamine hallucinations are eliminated [13]. For elective surgery, customary propofol increments are 50 mcg-1. kg repeated either to loss of lid reflex/loss of verbal response or to 60<BIS<75 with baseline EMG. This DCRM level is usually attained within 2-3 minutes. Starting with such an apparently homeopathic propofol dose quickly allows the anesthesiologist to determine an extremely sensitive patient and avoid prolonged emergence and, likely, less brain fog.

The benefit of incremental induction is creating a stable CNS level of propofol to protect from ketamine side effects, preservation of spontaneous ventilation, maintenance of SpO2, and not creating the difficult airway [14]. Incremental propofol induction most commonly preserves the tone in the masseter, genioglossus and orbicularis oris muscles, maintaining a patent airway. Absent a propofolbolus induction, baseline blood pressureis also maintained.

After observing the first 50 cases emerge without opioid rescue, it was reasonable to concludethe principle reason patients have pain after surgery is that they've had pain during surgery. The lack of opioid rescue continued over the next 1,214 patients [15] and through to the present day of more than a total 6,000 patients.

Dissociation, or immobility to noxious stimulation, results from mid-brain NMDA blockadelmmobility (i.e. dissociation) has beenconsistently observed in 100-pound female patients and 250-pound male patients with the same 50 mg ketamine dose.

Why does the effective dissociative dose of ketamine not appear to be related to body weight? The adult brain weighs approximately 3-4 pounds and doesn’t vary with body weight. The midbrain is a very small part of the adult brain, and the NMDA receptors are a very small part of the midbrain. Pre-stimulation NMDA block denies the cortex the knowledge of the intrusion of the outside world of danger.

Cognitive dissonance generated by thelack (or dramatically) reduced opioid rescue with pre-stimulation ketamine dose is so great that many, if not most, anesthesiologists will need to observe 10-20 cases to believe them. However, the PACU RNs will notice more quickly. Surgeons and patients' family members will be as impressed as the recovery personnel.Once the patient is protected as described above, the non-opioid, 50mg ketamine ‘miracle’ is achievable with propofol sedation, regional analgesia/propofol sedation, and general inhalational anesthesia ( Figure 5).

Postoperative Nausea & Vomiting (PONV)

Much has been written about postoperative nausea and vomiting (PONV). In 1996, Apfel identified the four most predictive PONV factors; namely, non-smoking, females, history of PONV, planned use of postoperative opioids [16]. Apfel subsequently referenced Friedberg's 1999 study [15] in his PONV chapter [17,18].

Apfel's PONV chapter is number 86 of 89 chapters in Millers' Anesthesia. While patients do not die from PONV, they only wish they were dead. Greater importance to PONV needs to be heeded by our profession as patient satisfaction now plays a role in government and other third party reimbursement.

The data for this five-year review documenting a 0.6% PONV rate (i.e. 7 of 1,264 patients) were collected by 1997 but not published until 1999 [15]. These patients turned out to be an Apfel-defined high PONV risk patient population that received no anti-emetics! No intra-operative opioids or inhalational ('stinky gases') agent were used [19]. Postoperative opioids were routinely prescribed but rarely used.

Analgesia was provided with adequate local analgesia. Spontaneous ventilation was preserved using only a single respiratory depressant, propofol, and scrupulously avoiding intra-operative opioids. no patients received neuromuscular blocking agents. This left the possibility of patient movement.

Patient movement under sedation is usually the cause for great stress on all involved with the surgery, especially the surgeon who may have pre-operatively injected the operative field with syringes of lidocaine and epinephrine. Observing vasoconstriction, the surgeon (incorrectly) surmises adequate analgesia is present and clamors for more sedation.

The anesthesiologist usually responds with a request for additional analgesia. Tempers rise leading to the inappropriate addition of opioids, benzodiazepines etc. or worse, the abandonment of sedation in favor of general anesthesia (GA) with muscle relaxants. None of these maneuvers treat the movement most accurately.

The presence or absence of an EMG spike on the DCRM enables a dispassionate discussion of what the patient most accurately (and minimally) needs to return the patient to the desired motionless condition. In the pre-DCRM era, all patient movement was treated as if it could be awareness and recall. As seen with the headless chicken, a brain is not necessary to generate movement ( Figure 6).

There exists no spinal reflex that can stimulate the EMG of the forehead frontalis muscle. Patient movement without an EMG spike can only be generated by sub-cortical stimulation. This Surgeon's Golden Rules ( Table 1) needs the anesthesiologist’s time preoperatively with the surgeon to assure success without increasing the known risks of GA. This author believes it is very difficult to accept GA risks for patients having surgery without medical indication; i.e. elective cosmetic surgery. A more enlightened approach is possible using the absence of the EMG spike with patient movement to refute the notion that the patient is 'too light' ( Figure 7) ( Table 1).

    Conclusion

When you can measure what you are speaking about, and express it in numbers, you know something about it; but when you cannot measure it, when you cannot express it in numbers, your knowledge is of a meager and unsatisfactory kind; it may be the beginning of knowledge, but you have scarcely, in your thoughts, advanced to the stage of science.

William Thompson, knighted Lord Kelvin.

Popular lectures and addresses 1891-1894

Less is more. - Mies van Der Rohe

Without direct cortical measurement of anesthetic effect, neither science nor minimally trespassing on patients’ physiology will occur. Predictably, problems like over and under-medication, postoperative pain management and PONV will continue to plague anesthesiologists and their patients while incurring avoidable costs. Propofol measurement to 60<BIS<75 with baseline EMG obviates the perceived need of the commonly used 2 mg midazolam premedication. Eliminating midazolam also eliminates prolonged emergence in sensitive and/or elderly patients.

Direct cortical response measurement enables anesthesiologists to treat patient requirements as the individuals they are as opposed to the 80% of patients in the middle of the bell curve. Doing so eliminates outliers, transforms every patients’ ‘mystery’ into an ‘open book test,’ and creates the basis for more humane, cost effective anesthesia care.

Over twenty-five years and in more than 6,000 patients, there has not been a single hospital admission for brain fog, postoperative pain management or PONV. Friedberg’s Triad does indeed appear to answer anesthesia’s persistent problems.

    Acknowledgment

Dr. Friedberg is the president and founder of the nonprofit Goldilocks Foundation. Neither he, nor the foundation, receives financial support from brain monitor makers. Dr. Barry Friedberg has been interviewed extensively about anesthesia and propofol by FOX, CNN, True TV, and People Magazine during the MichaelJackson murder trial. A board-certified anesthesiologist for 39 years, Dr. Friedberg developed propofol ketamine (PK) anesthesia in 1992 and made PKnumerically reproducible with the addition of the anesthesia brain monitor (aka Goldilocks anesthesia) in 1998. He has been published and cited inseveral medical journals and textbooks and was honored with a U.S. Congressional award for applying his methods on wounded soldiers in Afghanistan and Iraq.

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Monitoring the Depth of Anesthesia and Current Technology-Juniper Publishers

Introduction

General anesthesia (GA) is defined as a drug-induced loss of consciousness during which patients are not arousable, even by painful stimulation [1]. GA takes an important role in surgical procedures where an anesthetic overdose may lead to drug-associated toxicities, coma and even death; on the other hand a light anesthetic dose may lead to the well-known event of intraoperative awareness, which can cause sleep disorders, depression, night terrors, hospitals fears and post-traumatic stress disorder [2-4]. In this context, monitoring depth of anesthesia has become an important issue in anesthesiology.

Electroencephalographic signal (EEG) reflects the activity of the central nervous system and it has been widely used for monitoring depth of anesthesia. In general terms, the EEG of an anesthetized patient changes from high frequency, low amplitude when awake to low frequency, high amplitude when anesthetized; it is also noted that, during the anesthesia procedure the degree of EEG disorder is reduced. Therefore, the concept of entropy was introduced in EEG signal processing. Entropy is related to the complexity of a signal, and has been considered a promising measure of states of consciousness [5]. State Entropy (SE) and Response Entropy (RE) are indices provided by Datex-Ohmeda S/5TM entropy module (General Electric, Finland), which is currently a reference in EEG monitoring during general anesthesia [6,7]. SE and RE are based on spectral entropy computation over the Fourier spectrum; a description of the algorithm applied is available elsewhere [8]. The M-Entropy module is considered a reference in monitoring the depth of anesthesia based on EEG analysis, particularly the Response Entropy (RE) index, was considered a better predictor of patient response to painful stimuli than the Bispectral index (BIS) [9] .

Brain electrical activity indices provide an a dimensional number. Generally, a value between 40 and 60 is associated with an appropriate depth of anesthesia, higher values are associated with an awake patient and lower values with a very deep anesthesia. Although this information is useful, it should be used carefully, there could be cases in which the monitor may provide a paradoxical behavior, the next section introduce a report of a paradoxical cases identified at Clinica Universidad de La Sabana when using the Datex-Ohmeda indices.

EEG monitor and paradoxical behavior

There was a case in which the current technology (SE, RE) provide a parodoxical behaviour that did not match with the clinical assesment. A 49 years-old female patient, with procedure hysteroscopy and endometrial biopsy. In this case SE and RE show high values associated with an awake patient during the surgery (Figure 1).

Automatic impedance test from Datex-Ohmeda monitor showed no problem; this paradoxical behavior alerts the anesthesiology to increase doses of propofol from 2.5 to 3.0 mg.ml-1 and remifentanyl from 5.0 up to 7.0 ng.ml-1 at 1080s. After three minutes of the same paradoxical behavior, Datex- ohmeda indices were still inconsistent with the apparent state of the patient. The clinician decided to discarded SE and RE indices information for the rest of the procedure and based the decisions on standard monitoring and clinical assessment. Patient was followed-up by a phone interview 3 and 10 days after the procedure, no sign of dreams, intraoperative awareness or recall was reported.

A possible explanation for the paradoxical behaviour of Datex- ohmeda indices could be a failure to detect the interspersed low amplitude with high amplitude EEG pattern observed in upper graph of Figure 1, this pattern could be misinterpreted as a contaminated awake EEG resulting in a paradoxical increase in SE and RE, it can be observed that the signal reveals the burst supression pattern. Datex ohmeda indices return to a value associated with clinical state of the patient (40-60) 350s after the TCI was suspended at 2670s, and the EEG alpha spindles pattern becomes more clear.

Conclusion

In conclusion, there are cases in which current technology could misinterpreted EEG patterns. If the anesthesiologists are not aware of this situation, is likely that they deepen what is already deep anesthesia.It is important to realize that unexpectedly high quantitative EEG indices values are relatively common and may result in dangerous anesthetic drug overdose [10].

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Dexmedetomidine in Traumatic Brain Injury, Why Not?-Juniper Publishers

Editorial

Dexmedetomidine is an alpha-2 adrenoreceptor agonist with sedative, analgesic and anxiolytic properties. Since its release in the US market in late 1999, it has gained remarkable attention in the adult, pediatric and geriatric populations, predominantly because of its minimal respiratory depression. However, beyond its well-known properties, dexmedetomidine has recently been investigated for its potential in many other clinical scenarios, including neuroprotection, cardioprotection and renoprotection, with promising results [1].

Traumatic brain injuries, intracranial hemorrhage, intracranial malignancies, stroke, subarachnoid hemorrhage, and other conditions can precipitate the development of Cerebral edema and intracranial hypertension. Management options for intracranial hypertension include elevating the head of bed, normoventilation, eunatremia, pain control, reduction of noxious stimuli, and prevention of fever, hypoxemia, and hypotension. Sedation and analgesia with continuous infusions are considered first-line therapies to control intracranial hypertension in comatose patients who are intubated. The theoretical mechanism of continuous IV sedatives for ICP control is a safe reduction in cerebral blood flow and hence blood volume by reducing cerebral metabolic demand. Dexmedetomidine acts as a potent and specific alpha-2 adrenergic receptor agonist; it is unique in providing sedative-analgesic and anxiolytic effects without causing respiratory depression [2].

It has been hypothesized that global and focal cerebral ischemic events can be attenuated by the use of alpha-2 adrenoreceptor agonists. Catecholamine release is likely a factor contributing to injury. Catecholamines can potentially exacerbate neuronal injury by multiple mechanisms (catecholamines mediated increases in sensitivity to neurotransmitters such as glutamate; increased neuronal activity leading to expression of catabolic enzymes and possibly cell death due to excessive excitation; direct toxic effect of catecholamines on neurons; free radical formation) [3].

However, there is a significant and unresolved issue with respect to the safety and suitability of dexmedetomidine for use in patients who have or who are at risk for neurologic injuries. That issue is the matter of the uncertainty as to the effect of dexmedetomidine on the ratio of cerebral oxygen supply to cerebral oxygen demand (the ratio of cerebral blood flow CBF to cerebral metabolic rate CMR). The concern arises because the limited existing body of information suggests that dexmedetomidine might result in a reduction of the CBF/CMR ratio. The available information indicates that dexmedetomidine causes a reduction of CBF in humans. The effect of dexmedetomidine on CMR is less well documented [4].

Kendra J [5] and his colleagues suggested that Dexmedetomidine may avoid increases in the need for rescue therapy when used as an adjunctive treatment of refractory intracranial hypertension without compromising hemodynamics. He did his study on 23 patients undergo refractory intracranial hypertension. The primary objective of this review was to determine the change in quantified need for rescue therapy (hyperosmolar boluses and extraventricular drain [EVD] drainages). He used a dose of infusion 0.2 - 0.7 mcg/ kg/hours [5].

Ji-shen LUO [6] and his colleagues found that Dexmedetomidine could alleviate the stress as result of moderate and severe traumatic brain injury, and its anti-stress, and sedative effect was similar to those of propofol, but it's necessary to monitor the blood pressure. He did his study on 90 patients. He used a dose of bolus 0.5 - 1 mcg/kg on 30 minutes then infusion 0.2 - 0.6 mcg/kg/hours for 24 hrs [6].

Pajoumand M [7] and his colleagues cautioned that Dexmedetomidine was found to be associated with significantly more hypotension. He did his study on 198 patients. On the other hand, Hao J [8] and his colleagues results coincide with The sedation efficacy of DEX was superior to propofol in moderate and severe TBI, and was able to control excessive stress response after TBI better, and with more effect on blood pressure. He used the same protocol used by Ji-shen LUO [6].

Nakano T [9] and his colleagues suggested that Hypertension following the administration of high-dose dexmedetomidine is associated with cerebral hypoperfusion and the exacerbation of ischemic brain injury, possibly through alpha-2-induced cerebral vasoconstriction. He did his research on rat model. However Manhe Zhang [10] and his colleagues found that the mechanism by which dexmedetomidine reduces TBI is related to inhibition of autophagy in the hippocampal neurons of rats.

From all the above, I agreed with authors that Dexmedetomidine have a leading effect on reducing stress related secondary brain injury. However, Other beneficial effects in reducing apoptosis, and CBF/CMR ratio have limited existing evidences.

Conclusion

In Conclusion, Dexmedetomidine has a promising role in traumatic brain injury management, however hypotension must be avoided. Therefore, larger studies are needed to identify the role of Dexmedetomidine in traumatic brain injury and the effect on cerebral metabolic rate

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Postoperative Nausea and Vomiting: 168 Years in Review-Juniper Publishers

Abstract

DiLustro is the inventor of the multi-modal PONV Pressure Point therapy technique. Research and expanding use of this technique has proven to be a safe and effective multi-modal choice in PONV management. The company's acu-stimulation adhesive technique enhances anesthesiology benefits, such as, nausea and vomiting prophylaxis, elimination of expensive or risk-based rescue drug therapies and broader patient satisfaction, with no reported adverse effects. This evidence-based anesthetic-related technique provides an extended duration (72 hours) of PONV therapy to support Enhanced Recovery after Surgery (ERAS) protocol reimbursement practices.

Introduction

The introduction of volatile agents such as ether and chloroform in the 1840s was heralded as the most important medical innovation. However, the phenomenon of postoperative nausea and vomiting (PONV) became evident within only two years, and remains as a major complication for general anesthesia today. The first report on the devastating effect of PONV was published in 1848 by Dr. John Snow, a British anesthesiology pioneer who described his findings on this disturbing complication associated with surgery and anesthesia. Until his untimely death in 1858 at the age of 45 years, Dr. Snow was one of the foremost authorities in the administration of anesthesia [1].

During the ether era of 1846 to 1950, the incidence of PONV was reported to be as high as 75-80% [2]. During this time in an effort to reduce the incidence of PONV, neuroleptic drugs were considered the most efficacious pharmacotherapy because of the inherent anti-emetic properties of this drug class. The first prophylactic use of an anti-emetic drug derived from the neuroleptic phenothiazine drug class was introduced in the 1880s [2]. Neuroleptic phenothiazine drugs block receptors in the central nervous system's (CNS) dopamine pathways which mitigate the effects of nausea.

The Emergence of Anti-Emetic Therapy

Almost half a century later, the use of new neuroleptic class of promethazine drugs emerged to further reduce the incidence of PONV [3]. Promethazine pharmaceuticals have profound anti-emetic properties due to antagonizing histamine-1 receptors in the CNS. However, because of untoward sedative effects, the use of this drug class was very limited for postoperative antiemetic prophylaxis because it delayed emergence from general anesthesia. Twenty years later, the next phase of anti-emetic therapy emerged. The neuroleptic class of chlorpromazine drugs antagonized a variety of receptors in the CNS.3 Unfortunately the drug's neuroleptic effect elicits both sedation and hypotension which limited its use in PONV management.

The First Century of Anti-Emetic Therapy

After the discovery of anesthetic-induced PONV, clearly the distress of surgical patients were not positive experiences evidenced during the first 100 years ofthe practice of medicine. By 1950, anesthesia practice changed to reduce the residual effects of drugs that contributed to PONV. Six years later, halothane, a non-flammable volatile gas developed for general inhalational anesthesia was introduced, replacing noxious anesthetics such as ether. Halothane contributed to a substantially-reduced PONV incidence after emergence from inhalational general anesthesia. Over the next 25 years, halothane was commonly administered in clinical anesthesia practice [4]. During the 1980s in the US, the administration of these early inhalational anesthetic agents became less appealing and were gradually phased out as improved volatile agents were developed such as isoflurane, desflurane, or sevoflurane.

Evolution of PONV Prophylaxis

At the end of the 20th century, advancements in the prophylactic use of anti-emetic drug therapy had not progressed mainly because of the serious risks of drug side effects such as profound sedation. In the early 1990s, anesthetists preferred a novel anesthetic agent: propofol. This hypnotic drug is administered intravenously (IV) as an induction drug or total IV delivery for anesthetic maintenance. In addition, IV propofol has anti-emetic properties that help reduce the effects of PONV [4]. Propofol is still today's choice as a general anesthetic agent in contemporary anesthesia practice.

Novel Anti-Emetics

Fortunately, in the mid-1990s, anesthesiologists focused on the promising new class of anti-emetics, the 5-HT3-serotonin receptor antagonists introduced to oncologists for the treatment of chemotherapy-induced nausea and vomiting (CINV). These drugs block the 5-HT3-serotonin receptors, which are highly- specific emetogenic receptors in the chemoreceptor trigger zone (CTZ). Clinically, the 5-HT3-receptor antagonists produced an anti-emetic effect with little to no side effects, with a relatively good safety profile [5].

Since the mid-1990s, the traditional anti-emetic therapy chosen by most anesthesiologists and certified registered nurse anesthetists (CRNAs) to mitigate the incidence of PONV, include the serotonin 5-HT3-receptor antagonists such as ondansetron (Zofran®), granisetron (Kytril®) or dolasetron (Anzemet®). In addition, anesthesiologists and CRNAs use a multi-modal strategy that includes dexamethasone, a steroid drug that is known to have anti-emetic properties to enhance the efficacy of 5-HT3 prophylactic therapy. Due to multiple emetic receptors that can be stimulated during anesthesia, the management of PONV requires multi-modal strategies using a combination of antiemetic drugs to help ameliorate PONV such as 5-HT3-receptor antagonists, especially in the high-risk patient population [5]. These type of anti-emetics help block the serotonin receptors throughout the gut and CNS that trigger nausea and vomiting.

Short Duration of PONV Prophylaxis Efficacy

Much evidence published over the last 15 years describes the limited efficacy and duration of action of the traditional 5-HT3-receptor antagonists, including dexamethasone used in a multi-modal anti-emetic therapy regimen. Initially anesthetists thought that 5-HT3 antagonists should be preemptively administered, prior to the induction of anesthesia. However, because of the drug's relatively short duration of PONV efficacy, later practice evolved to administer prophylaxis just prior to emergence of anesthesia, at the completion of surgery during patient skin closure.

Comparatively, the traditionally standard use of 5-HT3- receptor antagonists, such as ondansetron (or in combination with dexamethasone), currently offer some PONV prevention as well as a higher safety profile compared to other prophylactic drugs. Despite the import of the evidence-based practice of multimodal anti-emetic drug prophylaxis, some surgical patients continue to experience protracted PONV symptoms which can also interfere with patients' recovery at home especially after outpatient surgery [6-8]. Clinically, an estimated 25%-30% of surgical patients are still impacted by PONV after general anesthesia subsequent to receiving prophylactic anti-emetic medications [9]. In addition, one-third or even up to 35%-49% of patients undergoing outpatient surgery experience nausea and vomiting after they are discharged. Largely because patients returning home from outpatient surgery do not have access to anti-emetic therapy [9,10].

Expanding Anti-Emetic Therapy

The relatively new phenomenon known as post-discharge nausea and vomiting (PDNV) has become a significant concern to practitioners because of the growing number of outpatient and short-stay surgical procedures. Anesthesiologists, CRNAs, and especially peri-operative nurses continue to be confronted with patients’ complications of PONV and PDNV, despite modifying dosages or combinations of anti-emetic therapy

After discharge from outpatient surgery, extended antiemetic benefits are not solving the PDNV problem at home.7 Clinical options for achieving anti-emetic efficacy in the postdischarge period include newer anti-emetics which are either very expensive, such as aprepitant (Emend®), palonesetron (Aloxi®), or transdermal scopolamine [11]. However, the scopolamine patch may have the potential of temporarily imposing adverse quality of life issues (i.e., blurred vision or extremely dry mouth) [12].

Enhancing patient satisfaction, providing cost-benefits and minimizing drug side effects are paramount for a worthy solution to the recalcitrant PONV problem. Use of other clinically- developed multi-modal PONV techniques that enable patients to overcome the anesthetic-induced difficulties associated with surgery can become part of a novel and efficacious multi-modal prophylaxis strategy for anti-emesis [13].

Effective emetic prophylaxis management today requires refinement for at-risk surgical patients who require enhanced protection against the episodic severity of further PONV and PDNV suffering. Current published PONV guidelines require an upgrade of additional PONV techniques to mitigate the effects of both post-operative problems. Over the last 15 years, evidence reveals that prophylactic drug therapy alone is not the complete solution in substantially preventing the incidence of PONV and PDNV. The PONV guidelines offer strategic insight into identifying at-risk surgical patients. However, the existing prophylactic multi-modal drug treatment strategy model has not resulted in a complete effect of a clear and definitive solution to extensively improving patient recovery from deleterious nausea and vomiting in the post-operative period [13].

The legacy of PONV prophylaxis today is compounded by the growing concern of PDNV occurrences at home for surgical patients. The implication for expanded anti-emetic coverage is readily apparent in view of current clinical PONV/PDNV events. Additional multi-modal PONV techniques are currently available to fill the vacuum of patient need due to inadequate efficacy of drug therapy. Clinically-proven and FDA approved prescription and/or over-the-counter (OTC) main stream, multi-modal PONV techniques implemented as part of the multi-modal anesthetic plan, would serve to improve overall PONV management conditions

The clear implication is that intervention other than further pharmacotherapy is necessary to reduce nausea and vomiting symptoms for surgery patients. Other clinically-proven, main stream multi-modal PONV techniques lead these efforts. Clearly a fundamental serious reevaluation is necessary to achieve an enhanced quality of PONV outcomes management compared to drug treatment options alone [13].

PONV Pressure Point Therapy

Pressure Point, Inc. is a global medical device company specializing in mainstream acu-point stimulation strips, which improve multi-modal anesthetic techniques associated with the complexity common problem of post-operative nausea and vomiting. The company introduced its Pressure Right© acupressure point-stimulation product in 2011 after receiving market clearance from the FDA as a prescribed technique representing an essential part of the anesthetic plan for surgery patients. In 2014, Pressure Point subsequently received market clearance as an OTC technique for the prevention of nausea and vomiting.

As part of a multi-modal strategy for patients undergoing laparoscopic surgery, a high quality, randomized, double-blind, sham-controlled study reported that the use of Pressure Right© demonstrated a statistically meaningful, absolute risk reduction of PONV for surgical patients as long as 72 hours postoperatively [14]. The study further confirmed the direct result of prophylaxis with Pressure Right© revealed a multi-modal PONV effect to substantially reduce the main stream requirements for expensive rescue-drug therapies. As a result, a broader patient satisfaction with PONV prevention was reported among Pressure Right© study subjects.

Prior to the introduction of the multi-modal Pressure Right© acu-stimulation strip in 2011 for the 72-hour prevention of PONV, a plethora of research had been published on the efficacy of acu-stimulation for PONV [14-16]. Several incipient versions of acu-stimulation offered significant benefits and few, if any risks. However, the early product models were limited in duration for multi-modal nausea prophylaxis for surgical use and patient suitability for PONV prevention.

Pressure Right's® adaptive adhesive technique uses 3M™ material that's been on the market since 1970, which is safe from skin irritation, blistering, or pain when applied to the skin for extended use.

The Pressure Right® randomized, double-blind, sham- controlled study effectively combined PC6 acustimulation and PONV antiemetic therapy versus antiemetic therapy and demonstrated improved PONV patient outcomes despite the use of an insensitive binary method (Yes or No) study response to assess postoperative nausea [14].

In a recent Cochrane review of PC6 acustimulation clinical data of at least 39 trials, 4622 participants, compared to sham treatment, it confirmed PC6 acustimulation techniques significantly reduced the incidence of nausea, vomiting and the need for rescue antiemetics postoperatively. The Cochrane author’s conclusion recommends more high-quality trials involving the combination of acustimulation and antiemetic drug therapy compared to drug prophylaxis to determine the combination’s clinical PONV therapy future impact [17].

Outside the US today, Pressure Point© has overseas distribution partners targeting the anesthetic market for prevention of PONV for at-risk surgical patients. Research and expanding use has proven Pressure Right© a high-quality competitive choice in PONV management.

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