The following review was published in the American Journal of Kidney Diseases.
Mixed Acid-Base Disturbances: Core Curriculum 2025
This is an open access full text review. It would be difficult to reduce it down to key points. It should be read in its entirety.
This topic was recently reviewed in the article linked here:
Acute upper gastrointestinal bleeding: state of the art review
Some key points follow.
Prevention
In critical illness, PPI therapy is recommended in selected high-risk patients.
Determinants of high risk were not specified in the review.
The review recommends outpatient PPI therapy for “high risk“ patients on DAP
or oral anticoagulants without specifying the risk factors.
Acute management
For patients with hemodynamic instability, a 500 mL crystalloid bolus is recommended
for initial volume management. Specific recommendations for continued volume
management were not given, but it can be implied that subsequent bolus therapies
and running IV fluids would be based on the patient's response and clinical judgment.
Transfusion threshold
A hemoglobin target of 7 g/dl is recommended as the threshold in general. A higher
threshold may be considered in ischemic heart disease or if there is active
exsanguination. The particulars regarding those conditions were not given.
New developments in risk assessment
Artificial intelligence based risk prediction and blood sensing capsules are promising
but not ready for prime time.
Management of antithrombotics
For patients on dual antiplatelet therapy with acute bleeding, the review recommends
temporary stoppage, except for continuation of aspirin when possible if the DAP was
given for maintenance of stent patency. In such cases, the other agent should be restarted
within 5 days if bleeding is controlled.
For patients on systemic anticoagulation, mere stoppage is indicated if there is
hemodynamic stability. If unstable, reversal is indicated.
Idarucizumab is recommended for reversal of dabigatran. For patients on anti-X a
agents, andexanet or four factor PCC is recommended.
Restart of systemic anticoagulants in patients with low thrombotic risk is recommended
at 7 days or later. For high thrombotic risk, restart is recommended within 3 days,
with bridging where applicable.
Tranexamic acid is generally not recommended.
Proton pump inhibitors
The literature regarding their use is somewhat controversial, but the review
acknowledges the common practice of giving an 80 mg bolus of pantoprazole followed
by an 8 mg per hour drip or an 80 mg bolus followed by 40 mg IV BID thereafter
EGD
For all GI bleeds, at 12 to 24 hours. If variceal is suspected, less than or equal to 12
hours.
Endotrachael intubation for EGD is not routinely recommended. The recommendation for
intubation applies only to patients who are obtunded, have massive hematimesis, or
evidence of poor airway protection.
In cases of rebleeding the following sequence is recommended: repeat
endoscopy ---> IR embolizqation ---> surgery.
Special considerations in variceal bleeding:
In general, many of the recommendations for non-variceal acute upper GI bleeding apply,
but there are some special considerations. The following points regarding variceal
bleeding are drawn from guidelines published in Hepatology linked here.
AASLD Practice Guidance on risk stratification and management of portal hypertension
Cirrhotic patients with upper GI bleeding should be treated as variceal until proven
otherwise.
Such patients should be started on vasoactive therapy (eg octreotide) and intravenous
antibiotic therapy immediately. Antibiotic therapy duration is to discharge or five days,
whichever is shorter.
RBC transfusion thresholds are similar to the recommendations above for GI bleeding
in general.
EGD within 12 hours is recommended for suspected variceal bleeding.
Early TIPS (same admission) is recommended in the following patients:
Those with a CTP score greater than 7 plus active bleeding at EGD.
Any patient with CTP greater than or equal to 10 regardless of whether active
bleeding is present.
Any patient who rebleeds or whose bleeding cannot be controlled endoscopically
If TIPS is not done, non-selective beta blocker administration is recommended.
Feeding is recommended once bleeding is controlled. The presence of varices or
bands is not a contraindication to feeding per os or via tube if indicated.
Dealing with coagulation parameters in cirrhosis:
The review, the guideline, and Up to Date are vague in this area. These
recommendations are best summarized as follows:
Generally, coagulation parameters need not (and should not) be corrected.
However, room is left for clinical judgment. (If it is a nonvariceal bleed,
Up to date recommends a platelet transfusion target of 50K).
Cryoprecipitate, either empirically (in active bleeding) or if fibrinogen is below
120K is stated to be “reasonable“ by the Up to Date authors. (The Up to Date
article is vague as to whether this recommendation applies to variceal bleeding,
non-variceal bleeding or both).
Thus, there is considerable room for clinical judgment. The underlying rationale
for the recommendations regarding coagulation management in cirrhosis is as follows:
Portal pressure, not hemostasis, is the principal driver of bleeding.
Due to the ”rebalanced hemostasis” characteristic of cirrhosis, coagulation parameters
are not predictive of bleeding risk.
The volume load of FFP needed to ”correct” an elevated INR will likely increase
portal pressure, thus aggravating bleeding.
There's insufficient evidence regarding 4 factor PCC in cirrhotic bleeding. In
general, it is not recommended unless for anticoagulant reversal.
This topic was reviewed in an article in the February 2024 issue of the American Journal of Medicine, linked here:
The Safe Use of Analgesics in Patients with Cirrhosis: A Narrative Review
Here are key points regarding various categories of analgesics:
Acetaminophen
Contrary to prevailing myth, acetaminophen is safe in patients with liver disease, including cirrhosis, provided dose limitations are applied.
In patients with liver disease who are actively consuming ethanol, short-term use up to two grams per day is permissible. For chronic use in patients not actively consuming alcohol a limit of two grams per day is also advised. Up to four grams per day may be permissible in cirrhotic patients not consuming alcohol for short-term use
NSAIDs
Systemic use is contraindicated for a variety of reasons. Topical diclofenac appears safe.
Opiates
In general, opiate use in patients with cirrhosis is associated with increased rates of hospital admission, increased length of stay, and an increased incidence of hepatic encephalopathy.
According to the review, they should be limited to short-term use and confined to short-acting preparations.
Gabapentin and pregabalin
These agents undergo virtually no hepatic metabolism and are considered safe in cirrhosis. Of course, like any drug with sedative effects, there is the potential to precipitate hepatic encephalopathy.
Duloxetine
This is widely used in pain treatment. However, adverse hepatic outcomes have been reported and it is considered contraindicated in liver disease. This recommendation is in keeping with product labeling.
Topical lidocaine is considered safe.
A recent review of the topic appeared in Lancet Infectious Disease, linked here:
Tetanus: recognition and management
General
Tetanus is rare in the developed world but worth discussing because it is a must not miss diagnosis.
Tetanus is caused by infection with Clostridium tetani. It produces a neurotoxin that is transported to the CNS retrogradely (by reverse axonal transport) where it blocks inhibitory neurotransmitter release thereby allowing unopposed motor activity. Four forms of tetanus are described: neonatal (not discussed here), localized (near the site of injury), cephalic (localized to the head and neck ), and generalized. Either of the localized forms can progress to generalized tetanus.
Epidemiology
Although considered rare in the developed world, 17 to 33 cases are diagnosed yearly in the United States. Inoculation sources can include any violation of skin integrity. Injection drug use, any type of wound, piercings, acupuncture, subQ or IM injections (either therapeutic or recreational), are possible sources. Up to 30% of cases are associated with no discernible history of a wound or injury. This epidemiology argues strongly for universal vaccination.
Clinical features
Clinical features include rigidity, spasm, trismus, opisthotonus, and dysphagia. Fever is often present but not invariably at presentation.
Diagnosis
Diagnosis is based on clinical features and confirmatory testing. A high index of suspicion is important due to non-textbook presentations (acute abdomen, dysphagia, stroke concerns, dystonia). The diagnostic test of choice is C tetani PCR from wound material. Anti tetanus toxin antibodies are also recommended, and while a low tighter is supportive of the diagnosis and high antibody levels rule against the diagnosis, this test is not definitive. Occasional cases have been reported in patients who had “protective” antibody titers.
Aspects of immunity
Natural infection does not confer immunity. Near elimination of the disease in the developed world is attributable to universal vaccination practices. Since there is no person to person transmission, herd immunity does not exist.
Treatment
Surgical debridement even for innocuous appearing wounds is indicated. Antibiotics should include metronidazole which according to low level evidence is associated with better overall outcomes. Antioxin in the form of tetanus immunoglobulin is indicated. Invasive mechanical ventilation is necessary in around 50% of patients and should this be required, primary tracheostomy is preferred.
Benzodiazepines are an important part of the treatment with diazepam as the benzo of choice. High doses and continuous drips are often necessary. Adjunctive neuromuscular blockade may be needed.
Dysautonomia
Dysautonomia is common and is a significant cause of mortality.
IV magnesium sulfate as a treatment for dysautonomia is associated with improved outcomes and a bolus/drip regimen is recommended, targeting serum levels of 2 to 4 mmole/L. Opiates have a significant role in the management of dysautonomia. Otherwise, vasoactive drugs as appropriate for the patient’s hemodynamic state may be indicated.
Finally, general symptomatic and supportive care to include fluids, nutritional support, stress ulcer prophylaxis, VTE prophylaxis along with skin and wound care are indicated.
It turns out to be a little of both. A number of reviews have addressed this. [1] [2] [3] Here are some of the key points:
The old maxim that cirrhotic patients are auto-anticoagulated is a myth. Severe liver disease is associated with a delicate balance between bleeding and clotting. In general, cirrhosis tends to be a hypercoagulable state. The relative risk for VTE in such patients has been estimated at around 2.
What are the mechanisms for the hypercoagulability of liver disease?
In primary hemostasis, while platelet numbers are often decreased these platelets tend to be hyper-functional. This is due to low levels of ADAM TS 13, correspondingly increased levels of VW factor and multifactorial endothelial dysfunction.
In secondary hemostasis, reasons for hypercoagulability include decreased levels of liver dependent natural anticoagulants such as protein C, protein S, and antithrombin. Factor VIII (not synthesized in the liver) tends to be increased.
There is also impaired fibrinolysis with increased levels of PAI-1 and decreased levels of plasminogen.
What are the clinical implications?
Traditional hemostatic tests are generally used but are of limited reliability. There's been increasing interest in global hemostatic tests such as viscoelastic assays which are conceptually more valid but are not yet ready for translation into clinical practice.
For low risk procedures, prophylactic hemostatic products peri-procedure are generally not indicated.
Antithrombotic treatments should be given in accordance with standard clinical indications recognizing a potentially increased risk of bleeding.
DOACs can be used in many patients but certain published restrictions apply.
When is warfarin favored over DOACs?
Valvular atrial fibrillation.
This term is becoming obsolete. For anticoagulation for stroke prevention in atrial fibrillation DOACs are contraindicated and warfarin favored in severe rheumatic mitral stenosis and mechanical prosthetic valves.
Liver disease.
If Child Pugh is C DOACs are not recommended. If B, apixaban and rivaroxaban can be used “with caution” (FDA labeling ). Child Pugh calculator.
Antiphospholipid syndrome.
Warfarin is favored (Up to Date).
Morbid obesity:
DOAC is okay for BMI up to 40. Above 40 rivaroxaban and apixaban are acceptable but other DOACs should be avoided.
History of gastrectomy or weight loss surgery:
Warfarin preferred. This review summarizes the rationale and recommendations regarding morbid obesity and patients who have had weight loss surgery.
In addition, certain drug interactions with DOACs are category X thus prohibiting use.
A few key points from the 2023 atrial fibrillation guidelines American College of Cardiology
New classification:
The old classification is maintained but it is encompassed in a broader classification outlining the stages of risk and /or the occurrence of atrial fibrillation.
Stage 1: at risk. This refers to the presence of risk factors such as obesity and hypertension.
Stage 2: pre atrial fibrillation encompassing structural abnormalities such as LAE or warning arrhythmias such as atrial ectopy.
Wiithin atrial fibrillation itself the traditional categories of paroxysmal persistent and permanent remain. Right above permanent atrial fibrillation is another designation referring to successful ablation.
Flexibility is built into the CHA₂DS₂-VASc score for anticoagulation decisions.
If the risk is intermediate there is considerable equipoise and shared decision making is advised.
Increased preference for early rhythm control.
There is an increased emphasis on early rhythm control especially in patients with heart failure and reduced ejection fraction. Catheter ablation via pulmonary vein isolation now he has a class 1 indication particularly in patients with who present with heart failure and reduced ejection fraction at the time of the onset of atrial fibrillation detection. Specifically:
Rhythm control recommended over rate control if decreased left ventricular function and persistent or high burden atrial fibrillation, class 1
If atrial fibrillation is symptomatic, class 2a.
Specific arrhythmias related to fibrillation have been defined.
Atrial tachycardia is defined as a rate greater than or equal to 100, non sinus. Mechanisms can be automaticity, triggered or micro reentry Atrial flutter. is considered any tachyarrhythmia that involves macro re-entry. Typical flutter involves macro reentry that goes through the cavo tricuspid isthmus. All others are considered atypical.
Caffeine avoidance is noted not to be beneficial.
The designation of valvular versus non-value or atrial fibrillation has become obsolete.
The recommendation now is that for a mechanical prosthesis or severe rheumatic mitral stenosis warfarin is recommended. DOACs are preferred for all other patients unless there are certain disease-related or pharmacokinetic contraindications.
In cases of cryptogenic stroke there is a 2a recommendation for extended monitoring. The guidelines do not specify the duration of monitoring.
For device detection of high rate episodes, (specifically pacemaker detection), stroke risk is believed to exist but believed to be less than that of clinical episodes.
If a high rate episode is detected and lasts greater than or equal to 5 minutes it is almost always atrial fibrillation. For device detection of high rate episodes lasting greater than or equal to 24 hours systemic anticoagulation is given a 2a recommendation. For the range of 5 minutes to 24 hours this same situation has a 2b recommendation. In both cases there is considered to be sufficient equipoise that shared decision making applies.
Atrial appendage occlusion devices such as the Watchman have a 2a recommendation if CHA₂DS₂-VASc is greater than or equal to 2 and anticoagulation is contraindicated.
For high bleeding risk but not a contraindication the device is given a 2b recommendation.
There are some changes in systemic anticoagulation recommendations for varying degrees of kidney disease.
Up to and including stage 3 systemic anticoagulation if otherwise recommended for atrial fibrillation has a class 1 recommendation. It drops to class 2a for stage 4 and to 2B if there is esrg/hd.
In atrial fibrillation with rheumatic valve disease or mechanical prosthesis for which vitamin K antagonist anticoagulation is recommended the CHA₂DS₂-VASc score does not apply.
The long-term rate control goal is an upper rate limit of 100-110 and has a 2a recommendation.
Acute rate control
If EF is greater than 40, IV beta blocker or non-dihydropyridine calcium blocker, class 1. Digoxin if above ineffective or contraindicated class 2a.
IV mag sulfate class 2a. It may be better than standard agents. Up to five grams is considered low dose. Occasionally one could use greater than or equal to 5 g. The main use is adjunctive.
Amiodarone if others ineffective or contraindicated, class 2b.
AVN ablation indications
AV node ablation if rate control is refractory to medication and the patient is otherwise a candidate, 2a. This will be combined with pacing obviously and initial lower rate limit, to avoid malignant ventricular arrhythmia, should be set at 80 to 90 with plans to program down by monthly decrements of 10 until 60 is reached.
Stroke prevention associatied with cardioversion
If atrial fibrillation could have been going on greater than or equal to 48 hours 3 weeks of anticoagulation first or tee prior to cardioversion and anticoagulation for greater than or equal to 4 weeks afterwards.
Drugs to maintain sinus rhythm long-term.
The guidelines are not very explicit about whether drugs should even be used in the first place. They merely say that such are “ reasonable “ for patients who are " not candidates for, or decline” ablation. Similarly those who prefer antiarrhythmic therapy to ablation are considered reasonable candidates. The implication is that you should probably do something to maintain sinus rhythm.
If normal EF and no structural heart disease and no coronary disease then fleccanide or propofanone 2a
Dronedarone 2a if no recent decompensated HR and if HF class II or better.
Dofetilide 2a if no long QT or torsades risks and no hypokalemia or hypomag, or tendency thereto.
Amiodarone is 2a but the agents above may be preferable.
Sotalol is 2b with the same precautions that apply to dofetilide.
In pts with prior MI, structural disease or EF less than or equal to 40% no recent decompensation or functional class III or worse, dronedarone is 2a.
When does antiarrhythmic therapy need to be administered in the hospital? And for how long?
Dofetilide 3 d
Sotolol, admit to hospital but the guideline does not specify how long.
ICs: Observe at least after the first dose.
PVI catheter ablation (pulmonary vein isolation ):
if antiarrhythmics not tolerated, contraindicated or not preferred, class 1. For younger patients with no or few comorbidities class 1 as first line even if the atrial fibrillation is paroxysmal.
For atrial flutter, class 1 ( it would be implied that this is typical flutter ). For a new diagnosis of atrial fibrillation in heart failure with reduced ejection fraction both at the same time early rhythm control is class 1 and ablation is said to be “ beneficial when appropriate” class 1.
This free full text review focuses on neurodegenerative synucleinopathies and briefly, in addition, touches on other disorders such as POTS, vasovagal syncope and inappropriate sinus tachycardia.
Synucleinopathies result from misfolded protein aggregates of α-synuclein. The normal function of α-synuclein in the nervous system is not well understood.
The synucleinopathies are parkinson disease, lewy body dementia, pure autonomic failure and multiple system atrophy. Any of these disorders can be accompanied by autonomic dysfunction.
Orthostatic hypotension, supine hypertension, or both may occur. All of the long-term consequences of hypertension may be associated with the supine hypertension seen in autonomic dysfunction. Use of a short acting antihypertensive administered at night is a suggested treatment strategy.
The
American thoracic Society has published a guideline for this
in the American Journal of Respiratory and Critical Care Medicine.
These are soft recommendations based on low-level evidence.
The
guideline does not address influenza or covid. For influenza,
the IDSA community-acquired pneumonia guidelines recommend influenza
PCR testing during flu season (in preference to antigen testing ).
The guidelines did not address covid-19 as there was
insufficient data at the time of the literature review.
The
guideline calls for viral PCR panel testing in the following groups
of patients: those with neutropenia, those undergoing active cancer
therapy, those with a transplant history, those with advanced HIV,
those with a history of chronic immunosuppression including systemic
corticosteroids, and those whose community-acquired pneumonia is
classified as severe.
Criteria for severity overlap with some of those just mentioned and include the presence of septic shock or need for mechanical ventilation. Absent these two conditions three of the following minor criteria denote severity: impaired respiratory physiology in the form of either a respiratory rate greater than 30 or a PO2 to Fio2 ratio below 250, multilobar infiltrates, altered mental status, BUN greater than 20, white blood cell count less than 4,000, platelet count less than 100,000, hypothermia less than 36.8 centigrade or hypotension requiring aggressive fluid resuscitation.
An issue from the American Journal of respiratory and Critical Care Medicine contains two articles and a related an editorial addressing this subject.
This study looked for evidence of aspergillus infection in patients diagnosed with VAP:
Rationale: Aspergillus infection in patients with suspected ventilator-associated pneumonia remains uncharacterized because of the absence of a disease definition and limited access to sensitive diagnostic tests.
Objectives: To estimate the prevalence and outcomes of Aspergillus infection in adults with suspected ventilator-associated pneumonia.
Methods: Two prospective UK studies recruited 360 critically ill adults with new or worsening alveolar shadowing on chest X-ray and clinical/hematological parameters supporting suspected ventilator-associated pneumonia. Stored serum and BAL fluid were available from 194 nonneutropenic patients and underwent mycological testing. Patients were categorized as having probable Aspergillus infection using a definition comprising clinical, radiological, and mycological criteria. Mycological criteria included positive histology or microscopy, positive BAL fluid culture, galactomannan optical index of 1 or more in BAL fluid or 0.5 or more in serum.
Measurements and Main Results: Of 194 patients evaluated, 24 met the definition of probable Aspergillus infection, giving an estimated prevalence of 12.4% (95% confidence interval, 8.1–17.8). All 24 patients had positive galactomannan in serum (n = 4), BAL fluid (n = 16), or both (n = 4); three patients cultured Aspergillus sp. in BAL fluid. Patients with probable Aspergillus infection had a significantly longer median duration of critical care stay (25.5 vs. 15.5 d, P = 0.02). ICU mortality was numerically higher in this group, although this was not statistically significant (33.3% vs. 22.8%; P = 0.23).
Conclusions: The estimated prevalence for probable Aspergillus infection in this geographically dispersed multicenter UK cohort indicates that this condition should be considered when investigating patients with suspected ventilator-associated pneumonia, including patient groups not previously recognized to be at high risk of aspergillosis.
Another study in the same issue looked at the prevalence of aspergillus in patients on mechanical ventilation with covid-19. They found it in over 20% of patients.
The
accompanying editorial cited additional evidence all of which
suggests that aspergillus infection is under-diagnosed in critically
ill patients.
Patients need not be immunosuppressed in
the traditional sense although the use of corticosteroids, even
short-term, is a major risk factor. The main use of corticosteroids
was for treatment of COPD exacerbations.
This review focuses mainly on gram-negative bacteria. Although it approaches the problem in light of the covid-19 pandemic it has general applicability.
First a few definitions.
ESKAPE microorganisms : Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp
Enterobacterales: new term for enterobacteriaceae
MDR: resistant to at least one antibiotic in three or more categories
XDR (extensive drug-resistant): resistant to at least one antibiotic in all but two or fewer categories
PDR (pan drug-resistant): resistant to all antibiotics
Difficult to treat resistant pathogens: resistant to front line agents and requiring second-line agents of greater toxicity and often lower efficacy (eg aminoglycosides, colistin).
Rates of infections due to ESBL producing organisms and carbapenemase producing organisms are rising. K. pneumoniae carbapenemase (KPC) producing bacteria are the ones predominant in the United States. The New Delhi Metallo-beta-lactamase (NDM) and the OXA-48 carbapenemase are rising in importance.
Acinetobacter is a complex and rising concern. From the review:
Finally,A. baumannii complex frequently causes nosocomial infections, particularly in ICUs where the incidence has increased over time. The SENTRY program evaluated the frequency of cases and anti-microbial susceptibility profiles of the A. baumannii collection from medical centers registered in this program [13]. This study showed that these isolates were recovered mainly from patients with pneumonia and bloodstream infections and evidenced reduced susceptibility to most antimicrobials tested. In all regions, colistin was the most active agent followed by minocycline.
Despite this seemingly grim picture the pipeline seems to have kept up with these trends reasonably well. Newer agents include:
Ceftolozane and tazobactam (Zerbaxa) Enhanced pseudomonas activity; activity against ESBL organisms but significant resistance rates; no activity against carbapenemase producing bacteria. (If used for intra abdominal infections coadministration of metronidazole is required).
Ceftazidime–avibactam (Avycaz) and imipenem–relebactam (Recarbrio) are active against most carbapenemase producing bacteria.
Not mentioned were fosfomycin (not yet available in IV form in the US) and omadacycline (Nuzyra). Omadacycline, though expected to be bacteriostatic, has an impressive spectrum. From another paper:
Omadacycline maintains activity against difficult-to-treat pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), Enterobacteriaceae that produce extended-spectrum β-lactamases (ESBLs) and carbapenemases, and multidrug-resistant (resistant to greater than or equal to 3 classes of agents) strains of Acinetobacter spp. and Stenotrophomonas maltophilia (2).
